Bromodomain inhibitors

ABSTRACT

The present invention provides for compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein A 1 , A 2 , A 3 , A 4 , X 1 , X 2 , Y 1 , L 1 , G 1 , R x , and R y  have any of the values defined thereof in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/008,994, filed Jan. 28, 2016, which is a divisional of U.S.application Ser. No. 13/828,285, filed Mar. 14, 2013, now U.S. Pat. No.9,296,741, granted Mar. 29, 2016, which is a continuation ofInternational PCT Application No. PCT/CN2012/086357, filed on Dec. 11,2012, which is a continuation in part of International PCT ApplicationNo. PCT/CN2011/002224, filed on Dec. 30, 2011. Each of the foregoingreferences are incorporated by reference in their entireties.

BACKGROUND

Bromodomains refer to conserved protein structural folds which bind toN-acetylated lysine residues that are found in some proteins. The BETfamily of bromodomain containing proteins is comprised of four members(BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs twobromodomains to recognize N-acetylated lysine residues found primarily,but not exclusively, on the amino-terminal tails of histone proteins.These interactions modulate gene expression by recruiting transcriptionfactors to specific genome locations within chromatin. For example,histone-bound BRD4 recruits the transcription factor P-TEFb topromoters, resulting in the expression of a subset of genes involved incell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976(2008)). BRD2 and BRD3 also function as transcriptional regulators ofgrowth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BETfamily members were recently established as being important for themaintenance of several cancer types (Zuber et al., Nature 478: 524-528(2011); Mertz et al; Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011);Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478:529-533 (2011)). BET family members have also been implicated inmediating acute inflammatory responses through the canonical NF-KBpathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resultingin the upregulation of genes associated with the production of cytokines(Nicodeme et al., Nature 468: 1119-1123, (2010)). In addition,bromodomain function has been implicated in kidney disease (Zhang, etal., J. Biol. Chem. 287: 28840-28851 (2012)). BRD2 function has alsobeen linked to a predisposition for dyslipidemia or improper regulationof adipogenesis, elevated inflammatory profiles and increasedsusceptibility to autoimmune diseases (Denis, Discovery Medicine 10:489-499 (2010)). The human immunodeficiency virus utilizes BRD4 toinitiate transcription of viral RNA from stably integrated viral DNA(Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain inhibitorshave also been shown to reactivate HIV transcription in models of latentT cell infection and latent monocyte infection (Banerjee, et al, J.Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt has an important role inspermatogenesis (Matzuk, et al., Cell 150: 673-684 (2012)). Accordingly,there is an ongoing medical need to develop new drugs to treat diseasesand indications involving bromodomain function, including BETbromodomain function.

SUMMARY

In one aspect the present invention provides for compounds of formula(I) or pharmaceutically acceptable thereof,

wherein

-   -   R^(x) is hydrogen or C₁-C₃ alkyl;    -   R^(y) is C₁-C₃ alkyl, —(C₂-C₃ alkylenyl)-OH, or C₁-C₃ haloalkyl;    -   X¹ is N or CR^(x1) wherein        -   R^(x1) is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1),            S(O)₂R^(dx1), —S(O)₂NR^(bx1)R^(cx1), G¹, C₁-C₆ haloalkyl, or            C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionally            substituted with one substituent selected from the group            consisting of OR^(ax1), SR^(ax1); S(O)R^(dx1), S(O)₂R^(dx1),            NR^(bx1)R^(cx1), —C(O)R^(ax1), —C(O)OR^(ax1),            —C(O)NR^(bx1)R^(cx1), —S(O)₂NR^(bx1)R^(cx1), and G^(x1);        -   R^(ax1), R^(bx1), and R^(cx1), at each occurrence, are each            independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a),            or —(C₁-C₆ alkylenyl)-G^(a);        -   R^(dx1), at each occurrence, are each independently C₁-C₆            alkyl, C₁-C₆ haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a);    -   X² is N or CR^(x2); wherein        -   R² is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax2),            —C(O)NR^(bx2)R^(cx2), —C(O)R^(dx2), —C(O)H, S(O)₂R^(dx2),            —S(O)₂NR^(bx2)R^(cx2), G^(x2), C₁-C₆ haloalkyl, or C₁-C₆            alkyl; wherein the C₁-C₆ alkyl is optionally substituted            with one substituent selected from the group consisting of            OR^(ax2), SR^(ax2), S(O)R^(dx2), S(O)₂R^(dx2),            NR^(bx2)R^(cx2), —C(O)R^(ax2), —C(O)OR^(ax2),            —C(O)NR^(bx2)R^(cx2), —S(O)₂NR^(bx2)R^(cx2), and G^(x2);        -   R^(ax2), R^(bx2), and R^(cx2), at each occurrence, are each            independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(b),            or —(C₁-C₆ alkylenyl)-G^(b);        -   R^(dx2), at each occurrence, is independently C₁-C₆ alkyl,            C₁-C₆ haloalkyl, G^(b), or —(C₁-C₆ alkylenyl)-G^(b);    -   Y¹ is N or CR^(u); wherein R^(u) is hydrogen, C₁-C₆ alkyl,        halogen, or C₁-C₆ haloalkyl;    -   A¹ is N or CR¹, A² is N or CR², A³ is N or CR³; and A⁴ is N or        CR⁴; with the proviso that zero, one, two, or three of A¹, A²,        A³, and A⁴ are N;    -   R¹, R³, and R⁴ are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, or        NO₂;    -   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(2a),        —OC(O)R^(2d), —OC(O)NR^(2b)R^(2c), —SR^(2a), —S(O)₂R^(2d),        —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a),        —C(O)NR^(2b)R^(2c), —NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d),        —N(R^(2e))S(O)₂R^(2d), —N(R^(2e))C(O)O(R^(2d)),        —N(R^(2e))C(O)NR^(2b)R^(2c), —N(R^(2e))S(O)₂NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(2a), —(C₁-C₆        alkylenyl)-OC(O)R^(2d), —(C₁-C₆ alkylenyl)-OC(O)NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆        alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d),        —(C₁-C₆ alkylenyl)-C(O)OR^(2a), —(C₁-C₆        alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d), —(C₁-C₆        alkylenyl)-N(R^(2e))S(O)₂R^(2d), —(C₁-C₆        alkylenyl)-N(R^(2e))C(O)O(R^(2a)), —(C₁-C₆        alkylenyl)-N(R^(2e))C(O)NR^(2b)R^(2c), —(C₁-C₆        alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c), and —(C₁-C₆        alkylenyl)-CN; R^(2a), R^(2b), R^(2c), and R^(2e), at each        occurrence, are each independently hydrogen, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2b), or C₁-C₆ alkyl wherein        the C₁-C₆ alkyl is optionally substituted with one substituent        selected from the group consisting of —OR^(z1), NR^(z1)R^(z2),        —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),        —S(O)₂NR^(z1)R^(z2), and G^(2b);    -   R^(2d), at each occurrence, is independently C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2b), or C₁-C₆ alkyl wherein        the C₁-C₆ alkyl is optionally substituted with one substituent        selected from the group consisting of —OR^(z1), NR^(z1)R^(z2),        —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),        —S(O)₂NR^(z1)R^(z2), and G^(2b);    -   R^(z1) and R^(z2), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   G^(x1), G^(x2), G^(a), G^(b), G^(2a), and G^(2b), at each        occurrence, are each independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl, and each of which is        independently unsubstituted or substituted with 1, 2, 3, 4, or 5        of R^(v);    -   L¹ is absent, CH₂, C(O), C(H)(OH), (CH₂)_(m)O, (CH₂)_(m)S(O)_(n)        wherein n is 0, 1, or 2; or (CH₂)_(m)N(R^(z)) wherein R^(z) is        hydrogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, (C₂-C₃ alkylenyl)-OH, or        unsubstituted cyclopropyl;    -   m is 0 or 1;    -   G¹ is C₁-C₆ alkyl, alkoxyalkyl, G^(1a) or —(C₁-C₆        alkylenyl)-G^(1a); wherein each G^(1a) is independently aryl,        heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each        G^(1a) is independently unsubstituted or substituted with 1, 2,        3, 4, or 5 of R^(w);    -   R^(v) and R^(w), at each occurrence, are each independently        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆        haloalkyl, —CN, oxo, —OR^(h), —OC(O)R^(i), —OC(O)NR^(j)R^(k),        —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k), —C(O)R^(h),        —C(O)-monocyclic heterocycle, —C(O)-monocyclic heteroaryl,        —C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R^(i),        —N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)),        —N(R^(h))C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆        alkylenyl)-OC(O)R^(i), —(C₁-C₆ alkylenyl)-OC(O)NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-S(O)₂R^(h), —(C₁-C₆        alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆ alkylenyl)-C(O)R^(h),        —(C₁-C₆ alkylenyl)-C(O)OR^(h), —(C₁-C₆        alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN;    -   R^(h), R^(j), R^(k), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and    -   R^(i), at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆        haloalkyl.

In one aspect the present invention provides for compounds of formula(I) or pharmaceutically acceptable thereof,

wherein

-   -   R^(x) is hydrogen or C₁-C₃ alkyl;    -   R^(y) is C₁-C₃ alkyl, —(C₂-C₃ alkylenyl)-OH, or C₁-C₃ haloalkyl;    -   X¹ is N or CR^(x1) wherein        -   R^(x1) is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1),            S(O)₂R^(dx1), —S(O)₂NR^(bx1)R^(cx1), G^(x), C₁-C₆ haloalkyl,            or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionally            substituted with one substituent selected from the group            consisting of OR^(ax1), SR^(ax1), S(O)R^(dx1), S(O)₂R^(dx1),            NR^(bx1)R^(x1), —C(O)R^(ax1), —C(O)OR^(ax1),            —C(O)NR^(bx1)R^(cx1), —S(O)₂NR^(bx1)R^(cx1), and G^(x1);        -   R^(ax1), R^(bx1), and R^(cx1), at each occurrence, are each            independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a),            or —(C₁-C₆ alkylenyl)-G^(a);        -   R^(dx1), at each occurrence, are each independently C₁-C₆            alkyl, C₁-C₆ haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a);    -   X² is N or CR^(x2); wherein        -   R^(x2) is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            —C(O)OR^(ax2), —C(O)NR^(bx2)R^(cx2), —C(O)R^(dx2),            S(O)₂R^(dx2), —S(O)₂NR^(bx2)R^(cx2), G^(x2), C₁-C₆            haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is            optionally substituted with one substituent selected from            the group consisting of OR^(ax2), SR^(ax2), S(O)R^(dx2),            S(O)₂R^(dx2), NR^(bx2)R^(cx2), —C(O)R^(ax2), —C(O)OR^(ax2),            —C(O)NR^(bx2)R^(cx2), —S(O)₂NR^(bx2)R^(cx2), and G^(x2);        -   R^(ax2), R^(bx2), and R^(cx2), at each occurrence, are each            independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(b),            or —(C₁-C₆ alkylenyl)-G^(b);        -   R^(dx2), at each occurrence, is independently C₁-C₆ alkyl,            C₁-C₆ haloalkyl, G^(b), or —(C₁-C₆ alkylenyl)-G^(b);    -   Y¹ is N or CR^(u); wherein R^(u) is hydrogen, C₁-C₆ alkyl,        halogen, or C₁-C₆ haloalkyl;    -   A¹ is N or CR¹, A² is N or CR², A³ is N or CR³; and A⁴ is N or        CR⁴; with the proviso that zero, one, two, or three of A¹, A²,        A³, and A⁴ are N;    -   R¹, R³, and R⁴ are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, or        NO₂;    -   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(2a),        —OC(O)R^(2d), —OC(O)NR^(2b)R^(2c), —SR^(2a), —S(O)₂R^(2d),        —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a),        —C(O)NR^(2b)R^(2c), —NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d),        —N(R^(2e))S(O)₂R^(2d), —N(R^(2e))C(O)O(R^(2d)),        —N(R^(2e))C(O)NR^(2b)R^(2c), —N(R^(2e))S(O)₂NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(2a), —(C₁-C₆        alkylenyl)-OC(O)R^(2d), —(C₁-C₆ alkylenyl)-OC(O)NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆        alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d),        —(C₁-C₆ alkylenyl)-C(O)OR^(2a), —(C₁-C₆        alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d), —(C₁-C₆        alkylenyl)-N(R^(2e))S(O)₂R^(2d), —(C₁-C₆        alkylenyl)-N(R^(2e))C(O)O(R^(2a)), —(C₁-C₆        alkylenyl)-N(R^(2e))C(O)NR^(2b)R^(2c), —(C₁-C₆        alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c), and —(C₁-C₆        alkylenyl)-CN;    -   R^(2a), R^(2b), R^(2c), and R^(2e), at each occurrence, are each        independently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆        haloalkyl, G^(2b), or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is        optionally substituted with one substituent selected from the        group consisting of —OR^(z1), NR^(z1)R^(z2), —C(O)OR^(z1),        —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1), —S(O)₂NR^(z1)R^(z2), and        G^(2b);    -   R^(2d), at each occurrence, is independently C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2b), or C₁-C₆ alkyl wherein        the C₁-C₆ alkyl is optionally substituted with one substituent        selected from the group consisting of —OR^(z1), NR^(z1)R^(z2),        —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),        —S(O)₂NR^(z1)R^(z2), and G^(2b); R^(z1) and R^(z2), at each        occurrence, are each independently hydrogen, C₁-C₆ alkyl, or        C₁-C₆ haloalkyl;    -   G^(x1), G^(x2), G^(a), G^(b) G^(2a), and G^(2b), at each        occurrence, are each independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl, and each of which is        independently unsubstituted or substituted with 1, 2, 3, 4, or 5        of R^(v);    -   L¹ is absent, CH₂, C(O), (CH₂)_(m)O, (CH₂)_(m)S(O)_(n) wherein n        is 0, 1, or 2; or (CH₂)_(m)N(R^(z)) wherein R^(z) is hydrogen,        C₁-C₃ alkyl, C₁-C₃ haloalkyl, (C₂-C₃ alkylenyl)-OH, or        unsubstituted cyclopropyl;    -   m is 0 or 1;    -   G¹ is G^(1a) or —(C₁-C₆ alkylenyl)-G^(1a); wherein each G^(1a)        is independently aryl, heteroaryl, heterocycle, cycloalkyl, or        cycloalkenyl, and each G^(1a) is independently unsubstituted or        substituted with 1, 2, 3, 4, or 5 of R^(w);    -   R^(v) and R^(w), at each occurrence, are each independently        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆        haloalkyl, —CN, oxo, —OR^(h), —OC(O)R^(i), —OC(O)NR^(j)R^(k),        —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k), —C(O)R^(h),        —C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R^(i),        —N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)),        —N(R^(h))C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆        alkylenyl)-OC(O)R^(i), —(C₁-C₆ alkylenyl)-OC(O)NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-S(O)₂R^(h), —(C₁-C₆        alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆ alkylenyl)-C(O)R^(h),        —(C₁-C₆ alkylenyl)-C(O)OR^(h), —(C₁-C₆        alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN;    -   R^(h), R^(j), R^(k), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and    -   R^(i), at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆        haloalkyl.

In another aspect, the present invention provides for methods fortreating or preventing disorders that are ameliorated by inhibition ofBET. Such methods comprise of administering to the subject atherapeutically effective amount of a compound of formula (I), alone, orin combination with a pharmaceutically acceptable carrier.

Some of the methods are directed to treating or preventing aninflammatory disease or cancer or AIDS.

In another aspect, the present invention relates to methods of treatingcancer in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, thecancer is selected from the group consisting of: acoustic neuroma, acuteleukemia, acute lymphocytic leukemia, acute myelocytic leukemia(monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,myelomonocytic and promyelocytic), acute t-cell leukemia, basal cellcarcinoma, bile duct carcinoma, bladder cancer, brain cancer, breastcancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic (granulocytic) leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent. In certain embodiments, the additionaltherapeutic agent is an anti-cancer agent. In particular embodiments,the additional therapeutic agents are selected from the group consistingof cytarabine, bortezomib, and 5-azacitidine.

In another aspect, the present invention relates to methods of treatinga disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said disease or condition is selected from the group consistingof: Addison's disease, acute gout, ankylosing spondylitis, asthma,atherosclerosis, Behcet's disease, bullous skin diseases, chronicobstructive pulmonary disease (COPD), Crohn's disease, dermatitis,eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis. In certainembodiments, the methods further comprise administering atherapeutically effective amount of at least one additional therapeuticagent. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent.

In another aspect, the present invention relates to methods of treatinga chronic kidney disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingan acute kidney injury or disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said acute kidney injury or disease orcondition is selected from the group consisting of: ischemia-reperfusioninduced, cardiac and major surgery induced, percutaneous coronaryintervention induced, radio-contrast agent induced, sepsis induced,pneumonia induced, and drug toxicity induced. In certain embodiments,the methods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent. In certainembodiments, the methods further comprise administering atherapeutically effective amount of at least one additional therapeuticagent.

In another aspect, the present invention relates to methods of treatingAIDS in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingobesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease,metabolic syndrome, hepatic steatosis, type II diabetes, insulinresistance, diabetic retinopathy or diabetic neuropathy in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods ofpreventing conception by inhibiting spermatogenesis in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

A further aspect of the invention provides the use of a compound offormula (I), alone or in combination with a second active pharmaceuticalagent, in the manufacture of a medicament for treating or preventingconditions and disorders disclosed herein, with or without apharmaceutically acceptable carrier.

Pharmaceutical compositions comprising a compound of formula (I), or apharmaceutically acceptable salt, alone or in combination with a secondactive pharmaceutical agent, are also provided.

DETAILED DESCRIPTION

Disclosed herein are compounds of formula (I)

wherein A¹, A², A³, A⁴, X¹, X², Y¹, L¹, G¹, R^(x), and R^(y) are definedabove in the Summary of the Invention and below in the DetailedDescription. Further, compositions comprising such compounds and methodsfor treating conditions and disorders using such compounds andcompositions are also disclosed.

Compounds disclosed herein may contain one or more variable(s) thatoccur more than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

a). Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “optionally a pharmaceuticallyacceptable carrier” refers to a single optional pharmaceuticallyacceptable carrier as well as one or more pharmaceutically acceptablecarriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond, optionally substituted with 1, 2,or 3 halogen atoms. The term “C₂-C₆ alkenyl” means an alkenyl groupcontaining 2-6 carbon atoms. Non-limiting examples of alkenyl includebuta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. Representative examples of alkenyleneinclude, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” refers to an alkylsubstituent containing from 1 to 6 carbon atoms and “C₁-C₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl,1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1to 4 carbon atoms or of 2 to 3 carbon atoms (C₂-C₃ alkylenyl). Examplesof alkylene and alkylenyl include, but are not limited to, —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbon atoms and containingat least one carbon-carbon triple bond, optionally substituted with 1,2, or 3 halogen atoms. The term “C₂-C₆ alkynyl” means an alkynyl groupof 2 to 6 carbon atoms. Representative examples of alkynyl include, butare not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples ofthe aryl groups include dihydroindenyl, indenyl, naphthyl,dihydronaphthalenyl, and tetrahydronaphthalenyl. The bicyclic aryls areattached to the parent molecular moiety through any carbon atomcontained within the bicyclic ring systems and can be unsubstituted orsubstituted.

The term “cycloalkyl” as used herein, refers to a radical that is amonocyclic cyclic alkyl, a bicyclic cycloalkyl, or a spiro cycloalkyl.The monocyclic cycloalkyl is a carbocyclic ring system containing threeto eight carbon atoms, zero heteroatoms and zero double bonds. Examplesof monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is amonocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. Themonocyclic and the bicyclic cycloalkyl groups may contain one or twoalkylene bridges, each consisting of one, two, three, or four carbonatoms in length, and each bridge links two non-adjacent carbon atoms ofthe ring system. Non-limiting examples of bicyclic ring systems includebicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). A spirocycloalkyl is a monocyclic cycloalkyl wherein two substituents on thesame carbon atom of the monocyclic cycloalkyl ring together with saidcarbon atom form a second monocyclic cycloalkyl ring. The monocyclic,the bicyclic, and the spiro cycloalkyl groups can be unsubstituted orsubstituted, and are attached to the parent molecular moiety through anysubstitutable atom contained within the ring system.

The term “cycloalkenyl” as used herein, refers to a monocyclic or abicyclic hydrocarbon ring radical. The monocyclic cycloalkenyl hasfour-, five-, six-, seven- or eight carbon atoms and zero heteroatoms.The four-membered ring systems have one double bond, the five- orsix-membered ring systems have one or two double bonds, and the seven-or eight-membered ring systems have one, two, or three double bonds.Representative examples of monocyclic cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is amonocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or amonocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. Themonocyclic or bicyclic cycloalkenyl ring may contain one or two alkylenebridges, each consisting of one, two, or three carbon atoms, and eachlinking two non-adjacent carbon atoms of the ring system. Representativeexamples of the bicyclic cycloalkenyl groups include, but are notlimited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyls can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems, and can be unsubstituted orsubstituted.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkylgroup, as defined herein, in which one, two, three, four, five or sixhydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl” meansa C₁-C₃ alkyl group, as defined herein, in which one, two, or threehydrogen atoms are replaced by halogen. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl,difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl,trifluorobutyl, and trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means a radicalof a monocyclic heterocycle, a bicyclic heterocycle, and a spiroheterocycle. A monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered carbocyclic ring also containing at least oneheteroatom independently selected from the group consisting of O, N, andS. A three- or four-membered ring contains zero or one double bond, andone heteroatom selected from the group consisting of O, N, and S. Whentwo O atoms or one O atom and one S atom are present in a heterocyclicring, then the two O atoms or one O atom and one S atom are not bondeddirectly to each other. A five-membered ring contains zero or one doublebond and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of five-membered heterocyclic ringsinclude those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S andN; 1 S, and 2 N; 1 O and N; or 1 O and 2 N. Examples of 5-memberedheterocyclic groups include tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl,imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and3-pyrrolinyl. A six-membered ring contains zero, one, or two doublebonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of six-membered heterocyclic ringsinclude those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N;1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1Q and 1 N; and 1 O and 2 N. Examples of 6-membered heterocyclic groupsinclude tetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl,1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl,piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl,1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,1,1-dioxo-hexahydro-1-thiopyranyl, 1,1-dioxo-1λ⁶-thiomorpholinyl,thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-memberedrings contains zero, one, two, or three double bonds and one, two, orthree heteroatoms selected from the group consisting of O, N, and S.Representative examples of monocyclic heterocycles include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocycleis a monocyclic heterocycle fused to a phenyl group, or a monocyclicheterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle. Representative examplesof bicyclic heterocycles include, but are not limited to, benzopyranyl,benzothiopyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrano[3,4-b][1,4]oxazin-1 (5H)-yl. The monocyclic heterocycleand the bicyclic heterocycle may contain one or two alkylene bridges oran alkenylene bridge, or mixture thereof, each consisting of no morethan four carbon atoms and each linking two non adjacent atoms of thering system. Examples of such bridged heterocycle include, but are notlimited to, azabicyclo[2.2.1]heptyl (including2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.1]oct-8-yl,octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). A spiro heterocycle is amonocyclic heterocycle wherein two substituents on the same carbon atomof the monocyclic heterocycle ring together with said carbon atom form asecond ring system selected from a monocyclic cycloalkyl, a bicycliccycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle.Examples of spiro heterocycle include, but not limited to,6-azaspiro[2.5]oct-6-yl, 1′H,4H-spiro[1,3-benzodioxine-2,4′-piperidin]-1′-yl, 1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl, and1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic, and thespiro heterocycles can be unsubstituted or substituted. The monocyclic,the bicyclic and the spiro heterocycles are connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the ring systems. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized (e.g.1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally bequarternized.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl anda bicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen or onesulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. Thebicyclic heteroaryl consists of a monocyclic heteroaryl fused to aphenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, ora monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or amonocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclicheteroaryl fused to a monocyclic heterocycle. Representative examples ofbicyclic heteroaryl groups include, but are not limited to,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, phthalazinyl,2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups can be substituted or unsubstituted and are connected to theparent molecular moiety through any substitutable carbon atom or anysubstitutable nitrogen atom contained within the ring systems. Thenitrogen atom in the heteroaryl rings may optionally be oxidized and mayoptionally be quarternized.

The term “heteroatom” as used herein, means a nitrogen, oxygen, andsulfur.

The term “oxo” as used herein, means a ═O group.

If a moiety is described as “substituted”, a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another pharmaceutical agentor treatment in a particular subject or subject population. For examplein a human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

b. Compounds

Compounds of the invention have the general formula (I) as describedabove.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In compounds of formula (I), R^(x) is as defined in the Summary. Forexample, in certain embodiments, R^(x) is hydrogen or methyl. In certainembodiments, R^(x) is hydrogen.

R^(y), in compounds of formula (I), is as disclosed in the Summary. Forexample, in certain embodiments, R^(y) is C₁-C₃ alkyl (e.g. methyl,ethyl). In certain embodiments, R^(y) is methyl.

X¹ is as disclosed in the Summary. For example, in certain embodiments,X¹ is N. In certain embodiments, X¹ is CR^(x1). R^(x1) is as defined inthe Summary or embodiments herein. In certain embodiments, R^(x1) ishydrogen, C₂-C₆ alkenyl, —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1),—C(O)R^(dx1), G^(x1), or C₁-C₆ alkyl wherein the C₁-C₆ alkyl isoptionally substituted with one substituent selected from the groupconsisting of OR^(ax1), NR^(bx1)R^(x1), and G^(x1). In certainembodiments, R^(x1) is hydrogen, —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1),G^(x1), or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substitutedwith OR^(ax1). In certain embodiments, R^(x1) is hydrogen,—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), optionally substituted phenyl, orC₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted withOR^(ax1) In certain embodiments, R^(x1) is hydrogen, —C(O)OR^(ax1), or—C(O)NR^(bx1)R^(cx1). In certain embodiments, R^(x1) is hydrogen orunsubstituted C₁-C₆ alkyl. In certain embodiments, R^(x1) is—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), or C₁-C₆ alkyl substituted withOR^(ax1). In certain embodiments, R^(x1) is hydrogen or—C(O)NR^(bx1)R^(cx1). In certain embodiments, R^(x1) is hydrogen.R^(ax1), R^(bx1), R^(x1), R^(dx1), and G^(x1), are as disclosed in theSummary. For example, R^(ax1) and R^(bx1), are each independentlyhydrogen, C₁-C₆ alkyl (e.g. methyl, ethyl, isopropyl), or C₁-C₆haloalkyl (e.g. trifluoromethyl). In certain embodiments, R^(ax1) andR^(bx1), are each independently hydrogen or C₁-C₆ alkyl (e.g. methyl,ethyl, isopropyl). In certain embodiments, R^(ax1) and R^(bx1), are eachindependently hydrogen, methyl, or ethyl. R^(cx1), for example, ishydrogen, C₁-C₆ alkyl (e.g. methyl, ethyl, isopropyl), or C₁-C₆haloalkyl (e.g. trifluoromethyl, 2,2,2 trifluoroethyl), wherein theC₁-C₆ alkyl is optionally substituted with G^(x1). In certainembodiments, R^(cx1), for example, is hydrogen or C₁-C₆ alkyl (e.g.methyl, ethyl, isopropyl). In certain embodiments, R^(cx1), for example,is G^(x1) or C₁-C₆ alkyl substituted with G^(x1); wherein G^(x1) isthiazolyl, morpholinyl, piperazinyl, tetrahydrofuranyl, or phenyl, eachof which is optionally substituted with 1, 2, or 3 substituents selectedfrom the group consisting of C₁-C₃ alkyl and C₁-C₃ haloalkyl.

X² is as disclosed in the Summary. For example, in certain embodiments,X² is N. In certain embodiments, X² is CR^(x2). R^(x2) is as defined inthe Summary or embodiments herein. In certain embodiments, X² is C(O)Hor C₁-C₆ alkyl substituted with one G^(x2). In certain embodiments, X²is C(O)H or C₁-C₃ alkyl substituted with one G^(x2) wherein G^(x2) ispiperidinyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with 1, 2, or 3 C₁-C₃ alkyl. In certain embodiments, R² ishydrogen or unsubstituted C₁-C₆ alkyl (e.g. methyl). In certainembodiments, R^(x2) is hydrogen.

Y¹ is N or CR^(u). For example, in certain embodiments, Y¹ is N. Incertain embodiments, Y¹ is CR^(u). R^(u) is as defined in the Summaryand embodiments herein. For example, in certain embodiments, R^(u) ishydrogen or C₁-C₆ alkyl (e.g. methyl). In certain embodiments, R^(u) ishydrogen or C₁-C₃ alkyl (e.g. methyl). In certain embodiments, R^(u) ishydrogen or methyl. In certain embodiments, R^(u) is hydrogen.

A¹, A², A³, and A⁴ are as defined in the Summary. In certainembodiments, A¹ is CR¹, A² is CR², A³ is CR³, and A⁴ is CR⁴; or one ofA¹, A², A³, and A⁴ is N. In certain embodiments, A¹ is CR¹, A² is CR²,A³ is CR³, and A⁴ is CR⁴. In certain embodiments, one of A¹, A², A³, andA⁴ is N. In the embodiments that one of A¹, A², A³, and A⁴ is N, exampleof a group of compound includes, but is not limited to, those wherein A¹is CR¹, A² is CR², A³ is CR³, and A⁴ is N. In certain embodiments, twoof A¹, A², A³, and A⁴ are N, for example, A¹ is N, A² is CR², A³ is N,and A⁴ is CR⁴; or for example, A¹ is N, A² is CR², A³ is CR³, and A⁴ isN. In certain embodiments, three of A¹, A², A³, and A⁴ are N, forexample, A¹ is N, A² is CR², A³ is N, and A⁴ is N.

R¹, R³, and R⁴, are as defined in the Summary. For example, in certainembodiments, R¹, R³, and R⁴, are each independently hydrogen, C₁-C₆alkyl (e.g. methyl, ethyl), halogen (e.g. Br, F, or Cl), or CN. Forexample, in certain embodiments, R¹, R³, and R⁴, are each independentlyhydrogen, C₁-C₆ alkyl (e.g. methyl, ethyl), or C₁-C₆ haloalkyl (e.g.trifluoromethyl). In certain embodiments, R¹, R³, and R⁴, are eachindependently hydrogen or methyl. In certain embodiments, R¹, R³, and R⁴are hydrogen.

R² is as disclosed in the Summary. In certain embodiment, R², forexample, is halogen, haloalkyl (e.g. CF₃), or —(C₁-C₃ alkylenyl)-CN. Incertain embodiments, R², for example, is hydrogen, C₁-C₆ alkyl, NO₂,G^(2a), —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a),—C(O)NR^(2b)R^(2c), —NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d),—N(R^(2e))S(O)₂R^(2d), —N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(2a), —(C₁-C₆alkylenyl)-S(O)₂R^(2d), —(C₁-C₆ alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-C(O)R^(2d), —(C₁-C₆ alkylenyl)-C(O)OR^(2a), —(C₁-C₆alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)R^(2d), —(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d),or —(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c). In certainembodiments, R², for example, is hydrogen, or NO₂. In certainembodiments, R², for example, is G^(2a), —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a), —C(O)NR^(2b)R^(2c),—NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d), —N(R^(2e))S(O)₂R^(2d),—N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆alkylenyl)-OR^(2a), —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d), —(C₁-C₆alkylenyl)-C(O)OR^(2a), —(C₁-C₆ alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),—(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c). In certain embodiments, R², forexample, is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d),—C(O)NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d), —N(R^(2e))S(O)₂R^(2d),—N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d), —(C₁-C₆alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),—(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c). In certain embodiments, R², forexample, is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—N(R^(2e))S(O)₂NR^(2b)R^(2c). In certain embodiment, R², for example, is—S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)-S(O)₂R^(2d). In certain embodiment, R², for example, is—(C₁-C₃ alkylenyl)-S(O)₂R^(2d) wherein R^(2d) is C₁-C₃ alkyl. In certainembodiment, R², for example, is —(CH₂)—S(O)₂R^(2d) wherein R^(2d) ismethyl or ethyl.

G^(2a), R^(2a), R^(2b), R^(2c), R^(2d), and R^(2e) are as disclosed inthe Summary and embodiments herein below.

In the embodiments wherein R² is G^(2a), G^(2a) is as disclosed in theSummary and embodiments herein. For example, in certain embodiments,G^(2a) is an optionally substituted heterocycle. In certain embodiments,G^(2a) is an optionally substituted monocyclic heterocycle. In certainembodiments, G^(2a) is 1,2-dioxido-1,2-thiazolidin-2-yl ortetrahydropyridinyl, each of which is optionally substituted. In certainembodiments, G^(2a) is optionally substituted1,2-dioxido-1,2-thiazolidin-2-yl. In certain embodiment, G^(2a) is arylor heteroaryl, each of which is optionally substituted. In certainembodiments, G^(2a) is optionally substituted phenyl. In certainembodiments, G^(2a) is pyridinyl or pyrazolyl, each of which isoptionally substituted. In certain embodiments, G^(2a) is unsubstituted.

In the embodiments wherein R² is —(C₁-C₆ alkylenyl)-G^(2a), G^(2a) is asdisclosed in the Summary and embodiments herein. For example, in certainembodiments, G^(2a) is a heterocycle or a heteroaryl, each of which isoptionally substituted. In certain embodiments, G^(2a) is a monocyclicheterocycle or a monocyclic heteroaryl, each of which is optionallysubstituted. In certain embodiments, G^(2a) is1,1-dioxido-1,2-thiazolidin-2-yl, pyrrolidinyl, morpholinyl, orpyrazolyl, each of which is optionally substituted. In certainembodiments, G^(2a) is unsubstituted. In certain embodiments, G^(2a) isoptionally substituted phenyl.

Where G^(2a) group is optionally substituted, it is, for example,optionally substituted with 1, 2, 3, 4, or 5 R^(v). R^(v) is asdescribed in the Summary and herein, for example, R^(v) is C₁-C₆ alkyl(e.g. methyl), halogen (e.g. F, Cl), C₁-C₆ haloalkyl, —CN, —NR^(j)R^(k),or —C(O)OR^(h); or for example, R^(v) is C₁-C₆ alkyl (e.g. methyl),halogen (e.g. F, Cl), or C₁-C₆ haloalkyl.

In the embodiments wherein R² is —S(O)₂R^(2d), R^(2d) is as disclosed inthe Summary and embodiments herein. In certain embodiments, R^(2d) isC₁-C₆ haloalkyl (e.g. CF₃), G^(2b), unsubstituted C₁-C₆ alkyl (e.g.methyl, ethyl, isopropyl), or C₁-C₆ alkyl substituted with one G^(2b)group; wherein G^(2b) is phenyl, monocyclic cycloalkyl, or monocyclicheterocycle, each of which is optionally substituted. In some suchembodiments, the G^(2b) group is optionally substituted with 1, 2, or 3R^(v) groups wherein R^(v) is as described in the Summary and herein,for example, each R^(v) is independently C₁-C₆ alkyl (e.g. methyl),halogen (e.g. F, Cl), C₁-C₆ haloalkyl, —OR^(h), —CN, or —NR^(j)R^(k), Incertain embodiments, R^(2d) is C₁-C₆ haloalkyl or unsubstituted C₁-C₆alkyl. In certain embodiments, R^(2d) is methyl or ethyl.

In the embodiments wherein R² is —S(O)₂NR^(2b)R^(2c), R^(2b) and R^(2c)are as disclosed in the Summary and embodiments herein. For example, incertain embodiments, R^(2b) is hydrogen or unsubstituted C₁-C₆ alkyl(e.g. methyl, ethyl), and R^(2c) is hydrogen, unsubstituted C₁-C₆ alkyl(e.g. methyl, ethyl), or C₁-C₆ haloalkyl (e.g. 2,2,2-trifluoroethyl,2-fluoroethyl). In certain embodiments, R^(2b) is hydrogen, and R^(2C)is optionally substituted phenyl, or R^(2c) is —C₁-C₃ alkyl substitutedwith one G^(2b) group wherein G^(2b) is optionally substitutedpyridinyl.

In the embodiments wherein R² is —C(O)R^(2d), R^(2d) is as disclosed inthe Summary and embodiments herein. For example, in certain embodiments,R^(2d) is G^(2b) wherein G^(2b) is as disclosed in the Summary andembodiments herein. For example, in certain embodiments, G^(2b) is anoptionally substituted heterocycle. In certain embodiments, G^(2b) is anoptionally substituted monocyclic heterocycle. In certain embodiments,G^(2b) is 1,1-dioxidothiomorpholin-4-yl, piperazinyl, piperidinyl,pyrrolidin-1-yl, or morpholin-4-yl, each of which is optionallysubstituted. Each G^(2b) is optionally substituted as described in theSummary and embodiments herein. For example, each G^(2b) isindependently unsubstituted or substituted with 1, 2, or 3 R^(v). R^(v)is as described in the Summary and embodiments herein. For example, eachR^(v) is independently C₁-C₆ alkyl (e.g. methyl), oxo, N(H)C(O)O(C₁-C₆alkyl), —CH₂—C(O)NR^(j)R^(k), —C(O)-monocyclic heterocycle, or—C(O)-monocyclic heteroaryl. In certain embodiments, each R^(v) isindependently C₁-C₆ alkyl (e.g. methyl), oxo, or N(H)C(O)O(C₁-C₆ alkyl).

In the embodiments wherein R² is —C(O)OR^(2a), R^(2a) is as disclosed inthe Summary and embodiments herein. For example, in certain embodiments,R^(2a) is hydrogen or unsubstituted C₁-C₆ alkyl (e.g. methyl, ethyl).

In the embodiments wherein R² is —C(O)NR^(2b)R^(2c), R^(2b) and R^(2c)are as disclosed in the Summary and embodiments herein. For example, incertain embodiments, R^(2b) is hydrogen or unsubstituted C₁-C₆ alkyl(e.g. methyl), and R^(2c) is hydrogen, G^(2b), C₁-C₆ haloalkyl (e.g.2,2-difluoroethyl), C₁-C₆ alkyl (e.g. methyl, ethyl) wherein the C₁-C₆alkyl is optionally substituted with one substituent selected from thegroup consisting of —OR^(z1), NR^(z1)R^(z2), and G^(2b). R^(z1), R^(z2),and G^(2b) are as defined in the Summary and embodiments herein. Forexample, in certain embodiments, G^(2b) is optionally substitutedphenyl. In certain embodiments, G^(2b) is a cycloalkyl, a heteroaryl, ora heterocycle, each of which is optionally substituted. In certainembodiments, G^(2b) is a monocyclic cycloalkyl, a monocyclic heteroaryl,or a monocyclic heterocycle, each of which is optionally substituted. Incertain embodiments, G^(2b) is pyridinyl, pyrimidinyl, indazolyl,indolyl, cyclopentyl, thiazolyl, 1,1-dioxidotetrahydrothienyl,tetrahydrofuranyl, piperazinyl, piperidinyl, or pyrrolidinyl, each ofwhich is optionally substituted. Each G^(2b) is optionally substitutedas described in the Summary and embodiments herein. For example, eachG^(2b) is independently unsubstituted or substituted with 1, 2, or 3R^(v). R^(v) is as described in the Summary and embodiments herein. Forexample, each R^(v) is independently C₁-C₆ alkyl (e.g. methyl), C₁-C₆haloalkyl, —OR^(h), —C(O)OR^(h), —S(O)₂R^(h), halogen, or oxo. Incertain embodiments, each R^(v) is independently C₁-C₆ alkyl (e.g.methyl) or oxo.

In the embodiments wherein R² is —NR^(2b)R^(2c), R^(2b) and R^(2c) areas disclosed in the Summary and embodiments herein. For example, incertain embodiments, R^(2b) and R^(2c) are each independently hydrogenor unsubstituted C₁-C₆ alkyl (e.g. methyl, ethyl).

In the embodiments wherein R² is —N(R^(2e))C(O)R^(2d), R^(2d) and R^(2e)are as disclosed in the Summary and embodiments herein. For example, incertain embodiments, R^(2e) hydrogen or unsubstituted C₁-C₆ alkyl (e.g.methyl, ethyl), and R^(2d) is unsubstituted C₁-C₆ alkyl (e.g. methyl,ethyl, tert-butyl) or C₁-C₆ haloalkyl (e.g. 2,2,2-trifluoroethyl).

In the embodiments wherein R² is —N(R^(2e))S(O)₂R^(2d), R^(2d) andR^(2e) are as disclosed in the Summary and embodiments herein. Forexample, in certain embodiments, R^(2e) is hydrogen or unsubstitutedC₁-C₆ alkyl (e.g. methyl, ethyl), and R^(2d) is unsubstituted C₁-C₆alkyl (e.g. methyl, ethyl) or C₁-C₆ haloalkyl (e.g.2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-dfluoroethyl). In certainembodiments, R^(2e) is hydrogen and R^(2d) is unsubstituted C₁-C₆ alkyl(e.g. methyl, ethyl). In certain embodiments, R^(2e) is C₁-C₆ haloalkyl,or C₁-C₆ alkyl substituted with one substituent selected from the groupconsisting of —OR^(z1), —NR^(z1)R^(z2), and G^(2b), and R^(2d) isunsubstituted C₁-C₆ alkyl (e.g. methyl, ethyl). In certain embodiments,R^(2e) is C₁-C₆ haloalkyl (e.g. 3,3,3-trifluoropropyl), or C₁-C₃ alkylsubstituted with one substituent selected from the group consisting of—OR^(z1), —NR^(z1)R^(z2), and G^(2b), and R^(2d) is unsubstituted C₁-C₆alkyl (e.g. methyl, ethyl), wherein G^(2b) is monocyclic cycloalkyl(e.g. cyclopropyl), monocyclic heterocycle (e.g. pyrrolidinylortetrahydrofuranyl), or monocyclic heteroaryl (e.g. pyridinyl), each ofwhich is optionally substituted.

In the embodiments wherein R² is —N(R^(2e))S(O)₂NR^(2b)R^(2c), R^(2b),R^(2c), and R^(2e) are as disclosed in the Summary and embodimentsherein. For example, in certain embodiments, R^(2b), R^(2c), and R^(2e)are each independently hydrogen or unsubstituted C₁-C₆ alkyl (e.g.methyl, ethyl).

In the embodiments wherein R² is —(C₁-C₆ alkylenyl)-OR^(2a), R^(2a) isas described in the Summary and embodiments herein. In certainembodiments R^(2a) is hydrogen. In certain embodiments, R² is —CH₂—OH or—CH₂CH₂—OH.

In the embodiments wherein R² is —(C₁-C₆ alkylenyl)-C(O)OR^(2a), R^(2a)is as described in the Summary and embodiments herein. For example,R^(2a) is hydrogen or unsubstituted C₁-C₆ alkyl (e.g. methyl, ethyl).

In the embodiments wherein R² is —(C₁-C₆ alkylenyl)-C(O)NR^(2b)R^(2c),R^(2b) and R^(2c) are as disclosed in the Summary and embodimentsherein. For example, in certain embodiments, R^(2b) and R^(2c) are eachindependently hydrogen or unsubstituted C₁-C₆ alkyl (e.g. methyl,ethyl).

In the embodiments wherein R² is —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),R^(2d) and R^(2e) are as disclosed in the Summary and embodimentsherein. For example, in certain embodiments, R^(2e) is hydrogen orunsubstituted C₁-C₆ alkyl (e.g. methyl, ethyl), and R^(2d) is C₁-C₆alkyl (e.g. methyl) optionally substituted with C(O)OR^(z1).

In the embodiments wherein R² is —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), R^(2d)is as disclosed in the Summary and embodiments herein. For example, incertain embodiments, R^(2d) is optionally substituted phenyl orunsubstituted C₁-C₆ alkyl. In certain embodiments, R^(2d) isunsubstituted C₁-C₃ alkyl. In certain embodiments, R^(2d) is methyl orethyl. In certain embodiments, R^(2d) is optionally substituted phenyl.

L¹ is as set forth in the Summary and embodiments herein. For example,in certain embodiments, L¹ is absent, CH₂, C(H)(OH), C(O), (CH₂)_(m)O,or (CH₂)_(m)N(R^(z)). For example, in certain embodiments, L¹ is CH₂,C(O), (CH₂)_(m)O, or (CH₂)_(m)N(R^(z)). In certain embodiments, L¹ is(CH₂)_(m)O or (CH₂)_(m)N(R^(z)). In certain embodiments, L¹ is(CH₂)_(m)O. In certain embodiments, L¹ is (CH₂)_(m)N(R^(z)).

The variable, m, is 0 or 1. In certain embodiments, m is 0. In certainembodiments, m is 1.

R^(z), is as set forth in the Summary and embodiments herein. Forexample, R^(z) is hydrogen or C₁-C₃ alkyl. In certain embodiments, R^(z)is hydrogen.

G¹ is as set forth in the Summary and embodiments herein. For example,G¹ is G^(1a)In certain embodiments, G¹ is —(C₁-C₆ alkylenyl)-G^(1a). Incertain embodiments, G¹ is C₁-C₆ alkyl or alkoxyalkyl. In certainembodiments, G¹ is C₁-C₆ alkyl (e.g. methyl, ethyl, isobutyl, or2,2-dimethylpropyl). In certain embodiments, G¹ is alkoxyalkyl.

G^(1a) is as defined in the Summary and embodiments herein. For example,in certain embodiments G^(1a) is aryl, heterocycle, or cycloalkyl, eachof which is optionally substituted. In certain embodiments G^(1a) isaryl, heterocycle, heteroaryl, or cycloalkyl, each of which isoptionally substituted. In certain embodiments G^(1a) is optionallysubstituted aryl. In certain embodiments G^(1a) is optionallysubstituted heterocycle. In certain embodiments G^(1a) is optionallysubstituted heteroaryl. In certain embodiments G^(1a) is optionallysubstituted cycloalkyl.

In the embodiments wherein G^(1a) is optionally substituted aryl,G^(1a), for example, is phenyl, naphthyl, or indanyl, each of which isoptionally substituted. In certain embodiments, G^(1a), for example, isoptionally substituted phenyl. In certain embodiments, G^(1a), forexample, is phenyl optionally substituted with one or two halogen (e.g.F). In certain embodiments, G^(1a) is

In certain embodiments, G^(1a) is unsubstituted phenyl or

In the embodiments wherein G^(1a) is optionally substituted heterocycle,examples of the heterocycle include, but are not limited to, oxetanyl,tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl),pyrrolidinyl, morpholinyl, piperidinyl, tetrahydrothiopyranyl, andtetrahydropyranyl (e.g. tetrahydropyran-4-yl, tetrahydropyran-3-yl),each of which (including the exemplary rings) is optionally substituted.

In the embodiments wherein G^(1a) is optionally substituted heteroaryl,G^(1a), for example, is pyrazolyl, pyridinyl, pyrimidinyl,2,1,3-benzothiadiazolyl, quinolinyl, or isoquinolinyl, each of which isoptionally substituted.

In the embodiments wherein G^(1a) is optionally substituted cycloalkyl(e.g. optionally substituted monocyclic cycloalkyl), examples of thecycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, andadamantyl, each of which is optionally substituted. In certainembodiments, G^(1a) is optionally substituted cycloalkyl. In certainembodiments, G^(1a) is unsubstituted cycloalkyl. In certain embodiments,G^(1a) is a substituted cycloalkyl. In certain embodiments, G^(1a) iscyclohexyl optionally substituted with 1 or two substituents selectedfrom the group consisting of C₁-C₃ alkyl (e.g. methyl), O(C₁-C₃ alkyl),and halogen. In certain embodiments, G^(1a) is cyclohexyl optionallysubstituted with 1 or two substituents selected from the groupconsisting of methyl and O(CH₃). In certain embodiments, G^(1a) is4,4-difluorocyclohexyl. In certain embodiments, G^(1a) is optionallysubstituted cyclopropyl. In certain embodiments, G^(1a) is unsubstitutedcyclopropyl.

The optional substituents of G^(1a) are as set forth in the Summary andembodiments herein. For example, each G^(1a) is independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 R^(w). In certainembodiments, R^(w) is, for example, C₁-C₆ alkyl-CN, halogen (e.g. F,Cl), oxo, C₁-C₆ haloalkyl (e.g. trifluoromethyl), —OR^(h), NR^(j)R^(k),—S(O)₂R^(h), —C(O)R^(h), —C(O)OR^(h), —C(O)NR^(j)R^(k), —(C₁-C₃alkylenyl)-OR^(h), or —(C₁-C₃ alkylenyl)C(O)NR^(j)R^(k). In certainembodiments, R^(w) is, for example, C₁-C₆ alkyl, —CN, halogen (e.g. F,Cl), or C₁-C₆ haloalkyl (e.g. trifluoromethyl). In certain embodiments,R^(w) is halogen, —OR^(h), or C₁-C₆ alkyl. In certain embodiments, R^(w)is halogen. In certain embodiments, R^(w) is F.

It is appreciated that compounds of formula (I) with combinations of theabove embodiments, including particular, more particular and preferredembodiments are contemplated. All embodiments of compounds of formula(I) formed by combining the substituent embodiments discussed above arewithin the scope of Applicants' invention, and some illustrativeembodiments of the compounds of formula (I) are provided below.

Accordingly, one aspect of the invention is directed to a group ofcompounds of formula (I) wherein L¹ is (CH₂)_(m)O and G¹ is G^(1a) andG^(1a) is as disclosed in the Summary and embodiments herein above.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); and X² is CR^(x2).

Yet other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR², and R^(y) is methyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl,and L¹ is CH₂, C(O), (CH₂)_(m)O, or (CH₂)_(m)N(R^(z)). In certainembodiments, L¹ is (CH₂)_(m)O. In yet other embodiments, L¹ is(CH₂)_(m)O and m is 0. In yet other embodiments, L¹ is (CH₂)_(m)O and mis 1. In certain embodiments, L¹ is (CH₂)_(m)N(R^(z)). In certainembodiments, L¹ is (CH₂)_(m)N(R^(z)) and m is 0. In yet otherembodiments, L¹ is (CH₂)_(m)N(R^(z)) and m is 1. R^(z) has values asdescribed in the Summary and embodiments herein above.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, and G¹ is —(C₁-C₆ alkylenyl)-G^(1a) wherein G^(1a) isoptionally substituted phenyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, and G¹ is —(C₁-C₆ alkylenyl)-G^(1a) wherein G^(1a) isoptionally substituted cycloalkyl. In some embodiments, G^(1a) isunsubstituted cyclopropyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, and G¹ is G^(1a).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substituted aryl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedphenyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedcycloalkyl (e.g. optionally substituted monocyclic cycloalkyl).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is N; X¹ is CR^(x1); X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedheterocycle (e.g. optionally substituted monocyclic heterocycle).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); and X² is CR^(x2).

Yet other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR^(x2), and R^(y) ismethyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,and L¹ is CH₂, C(O), (CH₂)_(m)O, or (CH₂)_(m)N(R^(z)). In certainembodiments, L¹ is (CH₂)_(m)O. In yet other embodiments, L¹ is(CH₂)_(m)O and m is 0. In yet other embodiments, L¹ is (CH₂)_(m)O and mis 1. In certain embodiments, L¹ is (CH₂)_(m)N(R^(z)). In certainembodiments, L¹ is (CH₂)_(m)N(R^(z)) and m is 0. In yet otherembodiments, L¹ is (CH₂)_(m)N(R^(z)) and m is 1. R^(z) has meaning asdescribed in the Summary and embodiments herein above.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)N(R^(z)), and G¹ is G^(1a) or —(C₁-C₆ alkylenyl)-G^(1a)wherein G^(1a) is phenyl, monocyclic heterocycle (e.g.tetrahydrofuranyl), or monocyclic cycloalkyl (e.g. cyclopropyl,cyclopentyl, cyclohexyl), each of which (including the exemplary rings)is optionally substituted.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)N(R^(z)), m is 0, R^(z) is hydrogen, and G¹ is G^(1a)wherein G^(1a) is phenyl, monocyclic heterocycle (e.g.tetrahydrofuranyl), or monocyclic cycloalkyl (e.g. cyclopropyl,cyclopentyl, cyclohexyl), each of which (including the exemplary rings)is optionally substituted.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR^(x), R^(y) ismethyl, L¹ is (CH₂)_(m)N(R^(z)), m is 0, R^(z) is hydrogen, and G¹ is—(C₁-C₆ alkylenyl)-G^(1a) wherein G^(1a) is monocyclic heterocycle (e.g.tetrahydrofuranyl), or monocyclic cycloalkyl (e.g. cyclopropyl,cyclopentyl, cyclohexyl), each of which (including the exemplary rings)is optionally substituted. In some embodiments, G¹ is —(C₁-C₃alkylenyl)-G^(1a) wherein G^(1a) is optionally substituted monocycliccycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl, each of which isoptionally substituted). In some embodiments, G¹ is —(CH₂)-G^(1a)wherein G^(1a) is optionally substituted monocyclic cycloalkyl (e.g.cyclopropyl, cyclopentyl, cyclohexyl, each of which is optionallysubstituted). In certain embodiments, G^(1a) is optionally substitutedis monocyclic heterocycle (e.g. optionally substitutedtetrahydrofuranyl). In certain embodiments, G^(1a) is optionallysubstituted cyclopropyl. In some embodiments, G^(1a) is unsubstitutedcyclopropyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, and G¹ is C₁-C₆ alkyl or alkoxyalkyl. In certainembodiments, G¹ is C₁-C₆ alkyl (e.g. methyl, ethyl, isobutyl, or2,2-dimethylpropyl). In certain embodiments, G¹ is alkoxyalkyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, and G¹ is —(C₁-C₆ alkylenyl)-G^(1a) wherein G^(1a) isoptionally substituted phenyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, and G¹ is —(C₁-C₆ alkylenyl)-G^(1a) wherein G^(1a) isoptionally substituted cycloalkyl. In some embodiments, G^(1a) isoptionally substituted cyclopropyl. In some embodiments, G^(1a) isunsubstituted cyclopropyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, and G¹ is G^(1a).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedaryl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedphenyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedcycloalkyl (e.g. optionally substituted monocyclic cycloalkyl).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is CR^(x1); X² is CR², R^(y) is methyl,L¹ is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedheterocycle (e.g. optionally substituted monocyclic heterocycle).

Yet other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), and R^(y) is methyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, andL¹ is CH₂, C(O), (CH₂)_(m)O, or (CH₂)_(m)N(R^(z)). In certainembodiments, L¹ is (CH₂)_(m)O. In yet other embodiments, L¹ is(CH₂)_(m)O and m is 0. In yet other embodiments, L¹ is (CH₂)_(m)O and mis 1. In certain embodiments, L¹ is (CH₂)_(m)N(R^(z)). In certainembodiments, L¹ is (CH₂)_(m)N(R^(z)) and m is 0. In yet otherembodiments, L¹ is (CH₂)_(m)N(R^(z)) and m is 1. R^(z) has meaning asdescribed in the Summary and embodiments herein above.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, and G¹ is G^(1a).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substituted aryl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedphenyl.

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedcycloalkyl (e.g. optionally substituted monocyclic cycloalkyl).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, G¹ is G^(1a), and G^(1a) is optionally substitutedheterocycle (e.g. optionally substituted monocyclic heterocycle).

Other examples of a group of compounds of formula (I) is directed tothose wherein Y¹ is CR^(u); X¹ is N; X² is CR^(x2), R^(y) is methyl, L¹is (CH₂)_(m)O, and G¹ is —(C₁-C₆ alkylenyl)-G^(1a) wherein G^(1a) isoptionally substituted cycloalkyl. In some embodiments, G^(1a) isoptionally substituted cyclopropyl. In some embodiments, G^(1a) isunsubstituted cyclopropyl.

Within each group of compounds of formula (I) described herein above,A¹, A², A³, and A⁴ have meanings as disclosed in the Summary andembodiments herein above.

For example, within each group of compounds of formula (I) describedherein above, examples of a subgroup include those wherein A¹ is CR¹, A²is CR², A³ is CR³, and A⁴ is CR⁴; or one of A¹, A², A³, and A⁴ is N.

Other examples of a subgroup include, but are not limited to, thosewherein A¹ is CR¹, A² is CR², A³ is CR³, and A⁴ is CR⁴.

Other examples of a subgroup include, but are not limited to, thosewherein one of A¹, A², A³, and A⁴ is N.

Yet other examples of a subgroup include, but are not limited to, thosewherein A¹ is CR¹, A² is CR², A³ is CR³, and A⁴ is N.

Yet other examples of a subgroup include, but are not limited to, thosewherein two of A¹, A², A³, and A⁴ are N.

Yet other examples of a subgroup include, but are not limited to, thosewherein A¹ is N, A² is CR², A³ is N, and A⁴ is CR⁴.

Yet other examples of a subgroup include, but are not limited to, thosewherein A¹ is N, A² is CR², A³ is CR³, and A⁴ is N.

Yet other examples of a subgroup include, but are not limited to, thosewherein three of A¹, A², A³, and A⁴ are N.

Yet other examples of a subgroup include, but are not limited to, thosewherein A¹ is N, A² is CR², A³ is N, and A⁴ is N.

Of all the groups and subgroups of compounds of formula (I) disclosed inthe preceding paragraphs, R¹, R², R³, R⁴, R^(x), R^(u); R^(x1), R^(x2),m, and the optional substituents of G¹ are as described in the Summaryand embodiments herein above.

For example, of all the groups and subgroups of compounds of formula (I)disclosed in the preceding paragraphs, R² is hydrogen, C₁-C₆ alkyl, NO₂,G^(2a), —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a),—C(O)NR^(2b)R^(2c), —NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d),—N(R^(2e))S(O)₂R^(2d), —N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(2a), —(C₁-C₆alkylenyl)-S(O)₂R^(2d), —(C₁-C₆ alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-C(O)R^(2d), —(C₁-C₆ alkylenyl)-C(O)OR^(2a), —(C₁-C₆alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)R^(2d), —(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d),or —(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c). In certainembodiments, R² is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c),—N(R^(2e))S(O)₂R^(2d), or —N(R^(2e))S(O)₂NR^(2b)R^(2c). In someembodiments, R² is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c),—N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆ alkylenyl)-S(O)₂R^(2d).

For example, of all the groups and subgroups of compounds of formula (I)disclosed in the preceding paragraphs, R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—N(R^(2e))S(O)₂NR^(2b)R^(2c), and R^(x) is hydrogen or methyl. Incertain embodiments, R^(x) is hydrogen.

For example, of all the groups and subgroups of compounds of formula (I)disclosed in the preceding paragraphs, R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—N(R^(2e))S(O)₂NR^(2b)R^(2c), R^(x) is hydrogen, and R^(x1) is hydrogen,—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), G^(x1), or C₁-C₆ alkyl wherein theC₁-C₆ alkyl is optionally substituted with OR^(ax1). In certainembodiments, R^(x1) is hydrogen, —C(O)OR^(ax1), or —C(O)NR^(bx1)R^(cx1).

For example, of all the groups and subgroups of compounds of formula (I)disclosed in the preceding paragraphs, R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—N(R^(2e))S(O)₂NR^(2b)R^(2c), R^(x) is hydrogen, R^(x1) is hydrogen,—C(O)OR^(ax1), or —C(O)NR^(bx1)R^(cx1), and R^(x2) is hydrogen.

For example, of all the groups and subgroups of compounds of formula (I)disclosed in the preceding paragraphs, R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)S(O)₂R^(2d), R^(x) is hydrogen, R^(x1) is hydrogen or—C(O)NR^(bx1)R^(cx1), and R² is hydrogen.

One aspect of the invention is directed to compounds of formula (I) orpharmaceutically acceptable salts thereof, wherein

R^(x) is hydrogen;

R^(y) is methyl;

Y¹ is CR^(u) wherein R^(u) is hydrogen;

X¹ is CR^(x1) wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1);

X² is CR^(x2) wherein R^(x2) is hydrogen;

L¹ is (CH₂)_(m)O wherein m is 0;

G¹ is G^(1a) or —(C₁-C₆ alkylenyl)-G^(1a), wherein G^(1a) is optionallysubstituted phenyl or optionally substituted cycloalkyl; and

R² is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—(C₁-C₆ alkylenyl)-S(O)₂R^(2d).

In some such embodiments, A¹ is CR¹, A² is CR², A³ is CR³, and A⁴ isCR⁴. In some further embodiments, A¹ is CR¹, A² is CR², A³ is CR³, andA⁴ is N.

Another aspect of the invention is directed to compounds of formula (I)or pharmaceutically acceptable salts thereof, wherein

R^(x) is hydrogen;

R^(y) is methyl;

Y¹ is CR^(u) wherein R^(u) is hydrogen;

X¹ is CR^(x1) wherein R^(x1) is hydrogen;

X² is CR^(x2) wherein R^(x2) is hydrogen;

L¹ is (CH₂)_(m)N(R^(z)) or wherein m is 0 and R^(z) is hydrogen;

G¹ is —(C₁-C₆ alkylenyl)-G^(1a), wherein G^(1a) is optionallysubstituted cycloalkyl; and

R² is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—(C₁-C₆ alkylenyl)-S(O)₂R^(2d).

In some such embodiments, A¹ is CR¹, A² is CR², A³ is CR³, and A⁴ isCR⁴. In some further embodiments, A¹ is CR¹, A² is CR², A³ is CR³, andA⁴ is N.

In one aspect the present invention provides for compounds of formula(I) or pharmaceutically acceptable thereof,

wherein

-   -   R^(x) is hydrogen or C₁-C₃ alkyl;    -   R^(y) is C₁-C₃ alkyl, —(C₂-C₃ alkylenyl)-OH, or C₁-C₃ haloalkyl;    -   X¹ is N or CR^(x1) wherein        -   R^(x1) is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1),            S(O)₂R^(dx1), —S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆            haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is            optionally substituted with one substituent selected from            the group consisting of OR^(ax1), SR^(ax1), S(O)R^(dx1),            S(O)₂R^(dx1), NR^(bx1)R^(x1), —C(O)R^(ax1), —C(O)OR^(ax1),            —C(O)NR^(bx1)R^(cx1), —S(O)₂NR^(bx1)R^(cx1), and G^(x1);        -   R^(ax1), R^(bx1), and R^(cx1), at each occurrence, are each            independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a),            or —(C₁-C₆ alkylenyl)-G^(a);        -   R^(dx1), at each occurrence, are each independently C₁-C₆            alkyl, C₁-C₆ haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a);    -   X² is N or CR^(x2); wherein        -   R^(x2) is hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,            —C(O)OR^(ax2), —C(O)NR^(bx2)R^(cx2), —C(O)R^(dx2),            S(O)₂R^(dx2), —S(O)₂NR^(bx2)R^(cx2), G^(x2), C₁-C₆            haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is            optionally substituted with one substituent selected from            the group consisting of OR^(ax2), SR^(ax2), S(O)R^(dx2),            S(O)₂R^(dx2), NR^(bx2)R^(cx2), —C(O)R^(ax2), —C(O)OR^(ax2),            —C(O)NR^(bx2)R^(cx2), —S(O)₂NR^(bx2)R^(cx2), and G^(x2);        -   R^(ax2), R^(bx2), and R^(cx2), at each occurrence, are each            independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(b),            or —(C₁-C₆ alkylenyl)-G^(b);        -   R^(dx2), at each occurrence, is independently C₁-C₆ alkyl,            C₁-C₆ haloalkyl, G^(b), or —(C₁-C₆ alkylenyl)-G^(b);    -   Y¹ is N or CR^(u); wherein R^(u) is hydrogen, C₁-C₆ alkyl,        halogen, or C₁-C₆ haloalkyl;    -   A¹ is N or CR¹, A² is N or CR², A³ is N or CR³; and A⁴ is N or        CR⁴; with the proviso that zero, one, two, or three of A¹, A²,        A³, and A⁴ are N;    -   R¹, R³, and R⁴ are each independently hydrogen, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, or        NO₂;    -   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(2a),        —OC(O)R^(2d), —OC(O)NR^(2b)R^(2c), —SR^(2a), —S(O)₂R^(2d),        —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a),        —C(O)NR^(2b)R^(2c), —NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d),        —N(R^(2e))S(O)₂R^(2d), —N(R^(2e))C(O)O(R^(2d)),        —N(R^(2e))C(O)NR^(2b)R^(2c), —N(R^(2e))S(O)₂NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(2a), —(C₁-C₆        alkylenyl)-OC(O)R^(2d), —(C₁-C₆ alkylenyl)-OC(O)NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆        alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d),        —(C₁-C₆ alkylenyl)-C(O)OR^(2a), —(C₁-C₆        alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-NR^(2b)R^(2c),        —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d), —(C₁-C₆        alkylenyl)-N(R^(2e))S(O)₂R^(2d), —(C₁-C₆        alkylenyl)-N(R^(2e))C(O)O(R^(2a)), —(C₁-C₆        alkylenyl)-N(R^(2e))C(O)NR^(2b)R^(2c), —(C₁-C₆        alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c), and —(C₁-C₆        alkylenyl)-CN;    -   R^(2a), R^(2b), R^(2c), and R^(2e), at each occurrence, are each        independently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆        haloalkyl, G^(2b), or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is        optionally substituted with one substituent selected from the        group consisting of —OR^(z1), NR^(z1)R^(z2), —C(O)OR^(z1),        —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1), —S(O)₂NR^(z1)R^(z2), and        G^(2b);    -   R^(2d), at each occurrence, is independently C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2b), or C₁-C₆ alkyl wherein        the C₁-C₆ alkyl is optionally substituted with one substituent        selected from the group consisting of —OR^(z1), NR^(z1)R^(z2),        —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),        —S(O)₂NR^(z1)R^(z2), and G^(2b);    -   R^(z1) and R^(z2), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   G^(x1), G^(x2), G^(a), G^(b) G^(2a), and G^(2b), at each        occurrence, are each independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl, and each of which is        independently unsubstituted or substituted with 1, 2, 3, 4, or 5        of R^(v);    -   L¹ is absent, CH₂, C(O), (CH₂)_(m)O, (CH₂)_(m)S(O)_(n) wherein n        is 0, 1, or 2; or (CH₂)_(m)N(R^(z)) wherein R^(z) is hydrogen,        C₁-C₃ alkyl, C₁-C₃ haloalkyl, (C₂-C₃ alkylenyl)-OH, or        unsubstituted cyclopropyl;    -   m is 0 or 1;    -   G¹ is G^(1a) or —(C₁-C₆ alkylenyl)-G^(1a); wherein each G^(1a)        is independently aryl, heteroaryl, heterocycle, cycloalkyl, or        cycloalkenyl, and each G^(1a) is independently unsubstituted or        substituted with 1, 2, 3, 4, or 5 of R^(w);    -   R^(v) and R^(w), at each occurrence, are each independently        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆        haloalkyl, —CN, oxo, —OR^(h), —OC(O)R^(i), —OC(O)NR^(j)R^(k),        —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k), —C(O)R^(h),        —C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R^(i),        —N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)),        —N(R^(h))C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆        alkylenyl)-OC(O)R^(i), —(C₁-C₆ alkylenyl)-OC(O)NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-S(O)₂R^(h), —(C₁-C₆        alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆ alkylenyl)-C(O)R^(h),        —(C₁-C₆ alkylenyl)-C(O)OR^(h), —(C₁-C₆        alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN;    -   R^(h), R^(j), R^(k), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and    -   R^(i), at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆        haloalkyl.

Compounds of formula (I) may contain one or more asymmetricallysubstituted atoms. Compounds of formula I may also exist as individualstereoisomers (including enantiomers and diastereomers) and mixturesthereof. Individual stereoisomers of compounds of formula I may beprepared synthetically from commercially available starting materialsthat contain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Compounds of formula I may also include the various geometric isomersand mixtures thereof resulting from the disposition of substituentsaround a carbon-carbon double bond, a carbon-nitrogen double bond, acycloalkyl group, or a heterocycle group. Substituents around acarbon-carbon double bond or a carbon-nitrogen double bond aredesignated as being of Z or E configuration and substituents around acycloalkyl or heterocycle are designated as being of cis or transconfiguration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Exemplary compounds of formula (I) include, but are not limited to:

-   6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(5-amino-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;-   2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]acetamide;-   N-methyl-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;-   ethyl    3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoate;-   3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoic    acid;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-3-yloxy)phenyl]methanesulfonamide;-   6-methyl-4-[2-(morpholin-4-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;-   3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(tetrahydrofuran-2-ylmethyl)benzamide;-   N-cyclopentyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;-   N-(2,2-difluoroethyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;-   3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(1,3-thiazol-2-yl)benzamide;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;-   3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;-   4-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide;-   N,N-dimethyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]sulfuric    diamide;-   N-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxypyridin-3-yl]methanesulfonamide;-   N-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;-   N-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]methanesulfonamide;-   6-methyl-4-[2-phenoxy-5-(1H-pyrazol-1-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]methanesulfonamide;-   N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(trifluoromethyl)phenoxy]phenyl}methanesulfonamide;-   N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   [4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetic    acid;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-3,3,3-trifluoropropanamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2,2-dimethylpropanamide;-   ethyl    4-(cyclopentylamino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate;-   4-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzyl]amino}-4-oxobutanoic    acid;-   4-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(benzyloxy)-5-(2-hydroxyethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   methyl    [4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetate;-   2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-ethylacetamide;-   2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N,N-dimethylacetamide;-   N-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]methanesulfonamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydrofuran-3-yl)benzamide;-   4-{2-(2,4-difluorophenoxy)-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(1-methyl-2-oxopyrrolidin-3-yl)benzamide;-   tert-butyl    {1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]pyrrolidin-3-yl}carbamate;-   4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylcarbonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylcarbonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]methanesulfonamide;-   6-methyl-4-[2-(morpholin-4-ylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide;-   N-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N′-methylsulfuric    diamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide;-   methyl    6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;-   methyl    1,6-dimethyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;-   ethyl    4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;-   6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic    acid;-   ethyl    6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;-   N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   ethyl    4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate;-   ethyl    4-[5-(ethylamino)-2-phenoxyphenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate;-   ethyl    4-{5-[ethyl(methylsulfonyl)amino]-2-phenoxyphenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate;-   6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic    acid;-   6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;-   6-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-phenoxyphenyl]methanesulfonamide;-   N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;-   6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one;-   N-ethyl-N,6-dimethyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;-   4-{4-[(ethylsulfonyl)amino]-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy}benzamide;-   6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;-   N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;-   6-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-{3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-phenoxyphenyl}methanesulfonamide;-   N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]propane-1-sulfonamide;-   N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]propane-1-sulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]propane-1-sulfonamide;-   3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzenesulfonamide;-   6-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   6-(cyclohexylamino)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   N-methyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]sulfuric    diamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamide;-   2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide;-   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide;-   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}propane-1-sulfonamide;-   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}-2,2,2-trifluoroethanesulfonamide;-   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}-N′-methylsulfuric    diamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]propane-1-sulfonamide;-   2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide;-   N-methyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]sulfuric    diamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide;-   N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;-   5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamide;-   N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamide;-   N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide;-   2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]propane-1-sulfonamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyrimidin-2-yl)benzamide;-   4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridin-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-(2,4-difluorophenoxy)-N-(1H-indazol-6-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-[2-(2,4-difluorophenoxy)-5-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-4-ylmethyl)benzamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide;-   4-(2,4-difluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   N-(3,4-difluorobenzyl)-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide;-   2-{4-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]piperazin-1-yl}-N,N-dimethylacetamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-2-ylmethyl)benzamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(3,4,5-trimethoxybenzyl)benzamide;-   4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   N-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-(2,4-difluorophenoxy)-N-[2-(1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   4-[2-(2,4-difluorophenoxy)-5-{[4-(furan-2-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   tert-butyl    {1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]piperidin-4-yl}carbamate;-   tert-butyl    4-{[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]amino}piperidine-1-carboxylate;-   4-[2-(2,4-difluorophenoxy)-5-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(4-chlorobenzoyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimidin-5-yloxy)phenyl]ethanesulfonamide;-   N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-methyl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamide;-   N-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide;-   N-[4-(2,2-dimethylpropoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one;-   4-[2-(2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(4-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(3-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(4-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile;-   4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile;-   6-methyl-4-{5-(methylsulfonyl)-2-[3-(trifluoromethyl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)phenyl]methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)phenyl]ethanesulfonamide;-   4-[2-(isoquinolin-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-6-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[2-chloro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[2-fluoro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   2-{4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}acetamide;-   4-[2-(3-aminophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylamino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(1-methylpiperidin-4-yl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,1,3-benzothiadiazol-4-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(isoquinolin-7-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(3,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-(4-methylphenoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2-methoxyphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{2-[(2-methylpyridin-3-yl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[3-(dimethylamino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[(3-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   2-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile;-   4-[2-(3-chloro-2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(naphthalen-1-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2-fluoro-5-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(5-fluoro-2-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-7-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(4-chloro-3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(pyridin-3-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,3-dihydro-1H-inden-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[4-(propan-2-yl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(isoquinolin-8-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(3,4,5-trifluorophenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(2-benzylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(biphenyl-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(4-oxocyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(3-fluorooxetan-3-yl)methoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   6-(cyclopropylmethoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   6-[(cyclopropylmethyl)amino]-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclobutyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopentylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopentyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(tetrahy    drofuran-3-ylmethoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxoimidazolidin-1-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2-cyclopropylethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cycloheptyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-(2-methylpropoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{2-[(2-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclohexylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{2-[2-(1-methylpyrrolidin-2-yl)ethoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[2-(morpholin-4-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(1-tert-butoxypropan-2-yl)oxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(1    S,4R)-bicyclo[2.2.1]hept-2-ylmethoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{2-[(1-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{2-[(4-methylcyclohexyl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclobutylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]cyclopropanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-methoxyethanesulfonamide;-   6-methyl-4-{5-(methylsulfonyl)-2-[tricyclo[3.3.1.1^(3,7)]dec-2-yloxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-[(cyclopropylmethyl)amino]-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   4-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   6-(2,4-difluorophenoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   4-[2-(cyclopropylmethoxy)-6-methylphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-4-ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(1,3-thiazol-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   ethyl    4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]piperidine-1-carboxylate;-   4-[2-ethoxy-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   N-[4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   4-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   4-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N,N,6-trimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   6-methyl-4-{5-(methylsulfonyl)-2-[4-(methylsulfonyl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;-   4-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,3-dihydro-1H-inden-2-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-[(dimethylamino)methyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-4-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methylpiperazin-1-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(phenylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(1,3-thiazol-2-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(tetrahydrofuran-3-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin-3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(prop-1-en-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(phenoxymethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide;-   4-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(dimethylamino)ethanesulfonamide;-   ethyl    4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate;-   4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]benzonitrile;-   4-[2-(cyclopropylmethoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[2-(2-hydroxyethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-{[3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   tert-butyl    4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate;-   4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-phenylbenzenesulfonamide;-   4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(pyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[3-(hydroxymethyl)phenoxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;-   N-[2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   tert-butyl    4-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate;-   4-[5-(6-aminopyridin-3-yl)-2-(cyclopropylmethoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[5-(ethylsulfonyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide;-   4-[4-(cyclopropylmethoxy)-3′-fluorobiphenyl-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   [4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetonitrile;-   N-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;-   4-[2-(cyclopropylmethoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(pyridin-2-ylmethyl)ethanesulfonamide;-   N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide;-   4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-[2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-{4-(2,4-difluorophenoxy)-3-[6-methyl-3-(morpholin-4-ylmethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-{6-methyl-3-[(4-methylpiperazin-1-yl)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;-   4-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4′-(cyclopropylmethoxy)-3′-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)biphenyl-3-carbonitrile;    and-   4-{2-(cyclopropylmethoxy)-5-[(4-hydroxypiperidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.-   In certain embodiments, a compound of formula I is selected from the    group consisting of:-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;-   N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;-   6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide;-   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide;    and-   N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;    or a pharmaceutically acceptable salt thereof.-   In certain embodiments, a compound of formula I is selected from the    group consisting of:-   4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   4-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one;-   6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;-   4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;    and-   N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide;-   or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention isN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide,or a pharmaceutically acceptable salt thereof.

Compounds of formula I can be used in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of formula (I) may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

General Synthesis

The compounds described herein, including compounds of general formula(I) and specific examples, may be prepared, for example, through thereaction routes depicted in schemes 1-5. The variables A¹, A², A³, A⁴,X¹, X², Y¹, L¹, G¹, R^(x), and R^(y) used in the following schemes havethe meanings as set forth in the summary and detailed descriptionsections unless otherwise noted.

Abbreviations used in the descriptions of the schemes and the specificexamples have the following meanings: n-BuLi or BuLi for n-butyllithium, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene, DIAD fordiisopropyl azodicarboxylate; DME for 1,2-dimethoxyethane, DMF fordimethylformamide, DMSO for dimethyl sulfoxide, EtOAc for ethyl acetate;mCPBA for 3-chloroperbenzoic acid, MeOH for methanol; Pd(PPh₃)₄ fortetrakis(triphenylphosphine)palladium(0), Preparative HPLC forpreparative HPLC; THF for tetrahydrofuran, TFA for trifluoroacetic acid,and HPLC for high performance liquid chromatography.

Compounds of general formula (I) may be prepared (a) by treating an arylhalide, an aryl mesylate, or an aryl triflate with an aryl boronic acidor derivatives thereof (e.g. boronic esters) under Suzuki couplingcondition (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J.Organomet. Chem. 1999, 576:147-148), and (b) removal of the protectinggroup (PG), as illustrated in Scheme 1. Thus coupling of compounds offormula (1) wherein R¹⁰¹ is Br, Cl, mesylate, or triflate with compoundsof formula (2) wherein R¹⁰² is boronic acid or derivatives thereof (e.g.boronic esters), or coupling of (1) wherein R¹⁰¹ is boronic acid orderivatives thereof (e.g. boronic esters) with compounds (2) whereinR¹⁰² is Br, Cl, mesylate, or triflate, provides intermediates of formula(3). Generally, the coupling reaction is effected in the presence of apalladium catalyst and a base, and optionally in the presence of aligand, and in a suitable solvent at elevated temperature (for example,at about 80° C. to about 150° C.). The reaction may be facilitated bymicrowave irradiation. Examples of the palladium catalyst include, butare not limited to, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate.Examples of suitable bases that may be employed include, but are notlimited to, carbonates or phosphates of sodium, potassium, and cesium;and cesium fluoride. Examples of suitable ligands include, but are notlimited to, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), and1,1′-bis(diphenylphosphanyl) ferrocene. Non-limiting examples ofsuitable solvent include methanol, dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran, andwater, or a mixture thereof.

Alternatively, treatment of formula (1) wherein R¹⁰¹ is Br, Cl, ortriflate with boronic acid of formula (4), followed by displacement ofthe fluoride atom in (4) with an appropriate alcohol or amine of formulaG¹-L¹-H wherein L¹ is O or NH, provides compounds of formula (3) orformula (I) wherein R^(x) is hydrogen.

Displacement of the fluorine with an alcohol or amine may be achieved ina solvent such as, but not limited to, dimethylsulfoxide,dimethylformamide, dioxane, or tetrahydrofuran, and in the presence of abase such as, but not limited to, cesium carbonate, potassium carbonate,or sodium hydride and at a temperature from about 40° C. to about 120°C.

The protecting group (PG) may be removed in situ during the displacementreaction or the coupling conditions described above.

Alternatively, removal of the protecting group (PG) to afford compoundsof general formula (I) wherein R^(x) is hydrogen can be accomplishedusing reaction conditions known generally to one skilled in the art, ormodifications thereof. For example, the tosyl protecting group can beremoved in the presence of a base such as, but not limited to, cesiumcarbonate, sodium hydroxide, or sodium hydride. The reaction isgenerally performed in the presence of a suitable solvent such as, butnot limited to, dimethylsulfoxide, methanol, or tetrahydrofuran, and ata temperature of about 40° C. to about 120° C. The benzyl protectinggroup may be removed by hydrogenation in the presence of a catalyst suchas, but not limited to, palladium on carbon and under hydrogenatmosphere. The reaction is typically performed in the presence of asolvent such as, but not limited to, methanol or ethyl acetate, and atabout room temperature.

Removal of the (trimethylsilyl)ethoxy)methyl protecting group can beachieved by treatment with a base such as, but not limited to, cesiumcarbonate or sodium hydride, or with a fluoride reagent such as, but notlimited to, TBAF (tetrabutylammonium fluoride). The reaction isgenerally performed in the presence of a suitable solvent such as, butnot limited to, dimethylsulfoxide, ethanol, or tetrahydrofuran, and at atemperature of about 40° C. to about 120° C. Removal of the(trimethylsilyl)ethoxy)methyl protecting group can also be achieved bytreatment with an mild acid such as but not limited to, aqueoushydrochloric acid. The reaction is generally performed in the presenceof a suitable solvent such as, but not limited to, ethanol, or methanol,and at a temperature of about 25° C. to about 80° C.

Conversion of compounds of formula (I) wherein R^(x) is hydrogen to (I)wherein R^(x) is C₁-C₃ alkyl can be achieved with an alkylating agent offormula R^(x)R¹⁰³ wherein R¹⁰³ is halogen, triflate, or mesylate.Generally, the reaction may be conducted in the presence of a base suchas, but not limited to, sodium hyride or potassium carbonate, and in asolvent such as, but not limited to, tetrhydrofuran ordimethylformamide, and at a temperature of about 40° C. to about 120° C.

Compounds of formula (1) wherein Y¹ is CR^(u), X¹ and X² are CH, andR^(u) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl may be prepared bygeneral synthetic methods as shown in Scheme 2.

Treatment of compounds of formula (6) wherein halo is Br, Cl, or I, with1,1-dimethoxy-N,N-dimethylmethanamine at elevated temperature (e.g.about 60° C. to about 100° ° C.), in the absence or presence of a base,and in a solvent such as, but not limited to, DMF, provide compounds offormula (7). Examples of suitable bases include, but not limited to,lithium or sodium methanolate. Catalytic hydrogenation of (7) in thepresence of a catalyst such as, but not limited to, Raney-Nickel andunder hydrogen atmosphere (about 30 psi) and in a solvent such as, butnot limited to, ethyl acetate, at about room temperature generallyaffords compounds of formula (8). Protection of the nitrogen atom withprotecting group such as, but not limited to, benzyl, tosyl, and(trimethylsilyl)ethoxy)methyl group can be derived from reaction with anappropriate halide in the presence of a strong base such as, but notlimited to, sodium hydride, to provide compounds of formula (9).

Treatment of (9) with an acid such as, but not limited to, hydrochloricacid or hydrobromic acid and in a solvent such as, but not limited to,dioxane or water, at about 40° C. to about 100° C., typically providescompounds of formula (10).

Alkylation of (10) with a halide or mesylate, in the presence of a basesuch as, but not limited to, sodium hydride, cesium carbonate, orpotassium carbonate, and in a solvent such as, but not limited to,dimethylformamide or dimethylsulfoxide at a temperature of about 0° C.to about 50° C. typically provides compounds of formula (11).

Treatment of the compounds of formula (11) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) generallyaffords compounds of formula (12). In general, the conversion may befacilitated by a palladium catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), or palladium(II)acetate, anoptional ligand such as, but not limited to,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), or1,1′-bis(diphenylphosphanyl) ferrocene, and a base such as, but notlimited to, carbonates, acetates, or phosphates of sodium, potassium,and cesium; and cesium fluoride. Non-limiting examples of suitablesolvents include methanol, dimethoxyethane, N,N-dimethylformamide,dimethylsulfoxide, dioxane, tetrahydropyran, and water, or a mixturethereof.

An approach to prepare compounds of formula (1) wherein Y¹ is N, R¹⁰¹ isCl, and X¹ and X² are CH, is outlined in Scheme 3.

Treatment of (13) with ammonium hydroxide at about 100° C. to about 150°C. can afford amines of formula (14).

Iodination of (14) with N-iodosuccinimide in a solvent such as, but notlimited to, acetonitrile or acetone, at a temperature of about 40° C. toabout 85° C., typically yields compounds of formula (15). Subsequentcoupling with(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane utilizingSuzuki coupling reaction conditions as described in Scheme 1 providescompounds of formula (16). Cyclization of (16) followed by protection ofthe nitrogen atom typically affords compounds of formula (17).

Cyclization of (16) may be accomplished in the presence of an acid suchas, but not limited to, acetic acid or hydrochloric acid and at anelevated temperature (e.g. about 50° C. to about 100° C.).

Compounds of formula (1) wherein Y¹ is N, R¹⁰¹ is Cl, X¹ is —COOR^(ax1)or —C(O)NR^(bx1)R^(cx1), R^(ax1), R^(bx1), and R^(cx1) are hydrogen orC₁-C₆ alkyl, and X² is CH may be prepared using the synthetic routeexemplified in Scheme 4.

Treatment of (15) with pyruvic acid in the presence of a palladiumcatalyst such as, but not limited to, palladium(II)acetate, and a basesuch as, but not limited to, DBU, and in a solvent such as, but notlimited to, DMF and at elevated temperature (e.g. at about 80° C. toabout 150° C.) generally results in acids of formula (18).Esterification of (18) to (19) may be accomplished by reactionconditions known to one skilled in the art, for example, by treatmentwith an alcohol under acidic condition. Subsequent protection of (19)using reaction conditions described in Scheme 2 for the conversion of(8) to (9) can provide for compounds of formula (20). Transformation of(20) to (21) may be accomplished by step-wise reaction of (a) hydrolysisof the ester to the corresponding acid and (b) conversion of the acid tothe corresponding amides.

The acid can be transformed to the appropriate acid chloride bytreatment with oxalyl chloride in the presence of catalytic amount ofDMF at about room temperature, and in a suitable solvent such as, butnot limited to, tetrahydrofuran or dichloromethane.

The resulting acid chloride may be converted to amides of formula (21)by treatment with an amine of formula HNR^(bx1)R^(cx1) in a solvent suchas, but not limited to, tetrahydrofuran, dimethylformamide, ordichloromethane at a temperature from about room temperature to about50° C., optionally in the presence of a base such as, but not limitedto, triethylamine, diisopropylethylamine, or potassium carbonate, andoptionally in the presence of a catalyst such as4-dimethylaminopyridine. Alternatively, the acid can be reacted with theamine of formula HNR^(bx1)R^(cx1) in a solvent such as, but not limitedto, tetrahydrofuran or dimethylformamide in the presence of a couplingreagent such as 1,1′-carbonyldiimidazole (CDI),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1),1,3-dicyclohexylcarbodiimide (DCC), polymer supported1,3-dicyclohexylcarbodiimide (PS-DCC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), in the presence or absence of a coupling auxiliary such as, butnot limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or1-hydroxybenzotriazole hydrate (HOBT). The reaction may be generallyconducted in the presence or absence of a base such as, but not limitedto, N-methyl morpholine, triethylamine, or diisopropylethylamine.

Scheme 5 demonstrates a general approach to the preparation of compoundsof formula (1) wherein Y¹ is CR^(u), R¹⁰¹ is halogen, X¹ is —COOR^(ax1)or —C(O)NR^(bx1)R^(cx1), R^(ax1), R^(bx1), and R^(cx1) are hydrogen orC₁-C₆ alkyl, and X² is CH.

An ester of formula (23) may be obtained from (a) treatment of (6) withdiethyl oxalate in the presence of a base such as, but not limited to,potassium ethoxide or sodium ethoxide, in a solvent such as, but notlimited to, potassium ethoxide or sodium ethoxide, in a solvent such as,but not limited to, ethanol, dioxane, or diethyl ether, and at atemperature of about 40° C. to about 80° C.; and (b) cyclization of theresulting (22) in the presence of iron and in ethanol and acetic acid,at a temperature of about 80° C. to about 100° C. Conversion of (23) to(26) can be achieved by employing reaction conditions discussed above.

An ethyl ester of formula (26) may subsequently be hydrolysed to thecorresponding acids. The resulting acids may be transformed to anappropriate ester or amide as described in Scheme 4.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be further processed inthe conventional manner, e.g. by eliminating the solvent from theresidue and further purified according to methodologies generally knownin the art such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

Pharmaceutical Compositions

This invention also provides for pharmaceutical compositions comprisinga therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I),alone or or in combination with a second active pharmaceutical agent,may be administered to the subjects orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form may be accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In certain embodiments, solid dosage formsmay contain from 1% to 95% (w/w) of a compound of formula I. In certainembodiments, the compound of formula I may be present in the soliddosage form in a range of from 5% to 70% (w/w). In such solid dosageforms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form can be a capsule, tablet, cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form. The quantity of active component in a unit dosepreparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mgto 100 mg, or from 1% to 95% (w/w) of a unit dose, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

The dose to be administered to a subject may be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc. In general, the dose equivalent of a compound is fromabout 1 μg/kg to 100 mg/kg for a typical subject.

For administration, compounds of the formula I can be administered at arate determined by factors that can include, but are not limited to, theLD₅₀ of the compound, the pharmacokinetic profile of the compound,contraindicated drugs, and the side-effects of the compound at variousconcentrations, as applied to the mass and overall health of thesubject. Administration can be accomplished via single or divided doses.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Treatment may be initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of formula I may also be administered in the form ofliposomes. Liposomes generally may be derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formmay contain, in addition to a compound of formula (I), stabilizers,preservatives, excipients and the like. Examples of lipids include, butare not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound described hereininclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Methods of Use

The compounds of formula I, or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions comprising a compound offormula I, or a pharmaceutically acceptable salt thereof, can beadministered to a subject suffering from a bromodomain-mediated disorderor condition. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the compounds of formula Ican be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. Also, the compounds described hereincan be administered by inhalation, for example, intranasally.Additionally, the compounds of formula I can be administeredtransdermally, topically, via implantation, transdermally, topically,and via implantation. In certain embodiments, the compounds of theformula I may be delivered orally. The compounds can also be deliveredrectally, bucally, intravaginally, ocularly, andially, or byinsufflation. Bromodomain-mediated disorders and conditions can betreated prophylactically, acutely, and chronically using compounds offormula I, depending on the nature of the disorder or condition.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of formula I.

A “bromodomain-mediated disorder or condition” is characterized by theparticipation of one or more bromodomains (e.g., BRD4) in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder or condition. Accordingly, compounds offormula I may be used to treat cancer, including, but not limited toacoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.

Further, compounds of formula I may be used to treat inflammatorydiseases, inflammatory conditions, and autoimmune diseases, including,but not limited to: Addison's disease, acute gout, ankylosingspondylitis, asthma, atherosclerosis, Behcet's disease, bullous skindiseases, chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat AIDS.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat chronic kidney disease or condition including, butare not limited to: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat acute kidney injury or disease or conditionincluding, but are not limited to: ischemia-reperfusion induced, cardiacand major surgery induced, percutaneous coronary intervention induced,radio-contrast agent induced, sepsis induced, pneumonia induced, anddrug toxicity induced.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat obesity, dyslipidemia, hypercholesterolemia,Alzheimer's disease, metabolic syndrome, hepatic steatosis, type IIdiabetes, insulin resistance, diabetic retinopathy or diabeticneuropathy.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to provide for male contraception in a male subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a male subject in need thereof.

The compounds of formula I can be co-administered to a subject. The term“co-administered” means the administration of two or more differentpharmaceutical agents or treatments (e.g., radiation treatment) that areadministered to a subject by combination in the same pharmaceuticalcomposition or separate pharmaceutical compositions. Thusco-administration involves administration at the same time of a singlepharmaceutical composition comprising two or more pharmaceutical agentsor administration of two or more different compositions to the samesubject at the same or different times.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to treat acancer, where examples of the agents include, such as radiation,alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors,activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variabledomain antibodies), leukemia viral oncogene homolog (ErbB2) receptorinhibitors, growth factor inhibitors, heat shock protein (HSP)-90inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies,immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs),intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2inhibitors, mammalian target of rapamycin inhibitors, microRNA's,mitogen-activated extracellular signal-regulated kinase inhibitors,multivalent binding proteins, non-steroidal anti-inflammatory drugs(NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors,proteosome inhibitors, purine analogs, pyrimidine analogs, receptortyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, smallinhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,ubiquitin ligase inhibitors, and the like, and in combination with oneor more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand.

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax), ABT-199, and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C₄,petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS 1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-STO1, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (famesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents to treat aninflammatory disease or condition, or autoimmune disease, where examplesof the agents include, such as methotrexate, tofacitinib,6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquine, pencillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled and local injection), beta-2 adrenoreceptor agonists(salbutamol, terbutaline, salmeteral), xanthines (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such asprednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNF□ or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1□converting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGF□), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab,adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib,sulfasalazine, methylprednisolone, meloxicam, methylprednisoloneacetate, gold sodium thiomalate, aspirin, triamcinolone acetonide,propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam,etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, prednisolone, cortisone,betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC familyinhibitors (such as Ruboxistaurin or AEB-071) and Mesopram. In certainembodiments, combinations include methotrexate or leflunomide and inmoderate or severe rheumatoid arthritis cases, cyclosporine and anti-TNFantibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) of the invention may beco-administered include the following: budenoside; epidermal growthfactor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1□ monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNF□ or IL-1 (e.g. NIK,IKK, or MAP kinase inhibitors); IL-1□ converting enzyme inhibitors; TNF□converting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGF□).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of Formula (I) can be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2(infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) andp55TNFRIgG (LENERCEPT™) inhibitors and PDE4 inhibitors. A compound ofFormula (I) can be combined with corticosteroids, for example,budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1□ convertingenzyme inhibitors and IL-ira; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolonesodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) may be co-administered include thefollowing: corticosteroids; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-□1a (AVONEX®; Biogen);interferon-□1b (BETASERON®; Chiron/Berlex); interferon □-n3) (InterferonSciences/Fujimoto), interferon-□ (Alfa Wassermann/J&J), interferon□1A-IF (Serono/Inhale Therapeutics), Peginterferon □ 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of Formula (I) can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of Formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNF□ or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1□ converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGF□).

A compound of Formula (I) may also be co-administered with agents, suchas alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,□-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) can be co-administered include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (HUMIRA), CA2 (infliximab), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) may be co-administered include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) may be co-administered include the following:albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) may be co-administered include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) may be co-administered include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), andefalizumab.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) may be co-administered include the following:NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam,indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib,valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids,for example, prednisone, prednisolone, budenoside, dexamethasone;cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolatemofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor,for example Cellcept®. A compound of Formula (I) may also be combinedwith agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine,Imuran® and agents which interfere with synthesis, production or actionof proinflammatory cytokines such as IL-1, for example, caspaseinhibitors like IL-10 converting enzyme inhibitors and IL-ira. Acompound of Formula (I) may also be used with T cell signalinginhibitors, for example, tyrosine kinase inhibitors; or molecules thattarget T cell activation molecules, for example, CTLA-4-IgG or anti-B7family antibodies, anti-PD-1 family antibodies. A compound of Formula(I) can be combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of Formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG(etanercept) and p55TNFRIgG (LENERCEPT™).

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine,lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine,and zidovudine. Examples of protease inhibitors include, but are notlimited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir,lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examplesof other retroviral drugs include, but are not limited to, elvitegravir,enfuvirtide, maraviroc and raltegravir.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to prevent ortreat type II diabetes, hepatic steatosis, insulin resistance, metabolicsyndrome and related disorders, where examples of the agents include,but are not limited to, insulin and insulins that have been modified toimprove the duration of action in the body; agents that stimulateinsulin secretion such as acetohexamide, chlorpropamide, glyburide,glimepiride, glipizide, glicazide, glycopyramide, gliquidone,rapaglinide, nataglinide, tolazamide and tolbutamide; agents that areglucagon-like peptide agonists such as exanatide, liraglutide andtaspoglutide; agents that inhibit dipeptidyl-peptidase IV such asvildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin andseptagliptin; agents that bind to the peroxisome proliferator-activatedreceptor gamma such as rosiglitazone and pioglitazone; agents thatdecrease insulin resistance such as metformin; agents that reduceglucose absorbance in the small intestine such as acarbose, miglitol andvoglibose.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to prevent ortreat acute kidney disorders and chronic kidney diseases, where examplesof the agents include, but are not limited to, dopamine, diuretics suchas furosemide, bumetanide, thiazide and the like, mannitol, calciumgluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol,cinacalcet and bardoxalone methyl.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to a male subjectto provide for male contraception.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES Example 16-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 1a(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine

5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) wasdissolved in dimethylformamide (300 mL), and lithium methanolate (6.07mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated to 100°C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95°C. for 16 hours. The reaction mixture was cooled to room temperature andwater was added carefully (300 mL, exothermic). The resultingprecipitate was collected by vacuum filtration, washed with water, anddried to provide the title compound (13.9 g, 45.9 mmol, 76% yield).

Example 1b 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added toRa—Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) ina stainless steel pressure bottle and stirred for 30 minutes at 30 psiand room temperature. The reaction mixture was filtered, andconcentrated. The residue was triturated with dichloromethane, and thesolid filtered to provide the title compound (5.82 g). The mother liquorwas evaporated and the residue triturated again with dichloromethane andfiltered to provide an additional 1.63 g of the title compound. Totalyield=7.45 g, 72% yield.

Example 1c 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235mL) was stirred at room temperature. To this solution was added sodiumhydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol), and thereaction mixture was stirred for 10 min. P-toluenesulfonyl chloride(9.35 g, 49.0 mmol) was then added portion-wise, and the mixture wasstirred at room temperature under nitrogen for 16 hours. The reactionmixture was quenched carefully with water and the resulting beige solidcollected by vacuum filtration on a Buchner funnel, and washed withwater. The solid was collected and dried in a vacuum oven at 50° C. toprovide 12.4 g (100%) of the title compound.

Example 1d 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A solution of Example 1c (12.4 g, 32.6 mmol) in dioxane (140 mL) wasstirred at room temperature. To this solution was added 4M HCl indioxane (140 mL). The reaction mixture was stirred at 40° C. for 16hours. The reaction mixture was cooled to room temperature andconcentrated. The residue was triturated with diethylether, filtered,and rinsed with additional diethylether and dried to provide the titlecompound (11.23 g, 30.6 mmol, 94% yield) as a beige solid.

Example 1e 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion)was added to a stirring solution of Example Id (11.2 g, 30.4 mmol) indimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane(2.27 mL, 36.5 mmol) was added and the solution was stirred at roomtemperature for 3 h. Upon addition of water (250 mL) a precipitateformed. The precipitate was collected by vacuum filtration, rinsed withwater (50 mL) and dried in a vacuum oven at 55° C. overnight to provide11.2 g of the title compound (96%).

Example 1f6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 1e (152 mg, 0.40 mmol), 2-phenoxyphenylboronic acid(0.111 g, 0.520 mmol, 1.3 equivalents), Pd(PPh₃)₄ (0.023 g, 5 mol %) andcesium fluoride (0.182 g, 1.2 mmol) in DME (3 mL) and methanol (1.5 mL)was heated under microwave condition (120° C., 30 minutes). To thismixture was added potassium carbonate (0.055 g, 0.40 mmol) and water (1mL) and the reaction mixture was reheated in the microwave oven at 120°C. for another 2 hours. The organic layer was separated and purified byflash chromatography (silica gel, ethyl acetate). The resulting materialwas triturated with acetone and filtered to provide 0.075 g of the titlecompound (59%). ¹H NMR (500 MHz, DMSO-d₆) δ 3.50 (s, 3H), 6.21-6.23 (m,1H), 6.88 (d, J=7.62 Hz, 2H), 6.99-7.04 (m, 2H), 7.24-7.30 (m, 5H),7.36-7.40 (m, 1H), 7.50 (dd, J=7.48, 1.68 Hz, 1H), 11.98 (s, 1H). MS(ESI+) m/z 317 (M+H)⁺.

Example 26-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 2a4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-oneMethod A:

Example 1e (0.687 g, 1.802 mmol), 2-fluoro-5-nitrophenylboronic acid(0.500 g, 2.70 mmol), Pd(PPh₃)₄ (0.104 g, 0.090 mmol) and sodiumcarbonate (2.70 mL, 5.41 mmol) were combined in DME (7 mL) and water (7mL) in a 20 mL microwave tube, sealed, sparged with nitrogen and heatedunder microwave at 120° C. for 30 minutes. The mixture was partitionedbetween EtAOc and water. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified byflash chromatography (silica gel, 0-100% ethyl acetate in hexanes) toprovide 0.41 g (52%) of the title compound.

Method B:

Example 1e (6.00 g, 15.7 mmol), 2-fluoro-5-nitrophenylboronic acid (5.82g, 31.5 mmol), Pd(PPh₃)₄ (0.909 g, 0.787 mmol) and sodium carbonate(3.34 g, 31.5 mmol) were combined in toluene (60 mL), ethanol (15 mL)and water (15 mL) and the mixture was degassed and left under nitrogen.The reaction mixture was heated at 90° C. overnight, and then cooled toroom temperature. The mixture was partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried (MgSO₄), filteredand concentrated. The crude product was purified by flash chromatography(silica gel, 20-50% ethyl acetate in hexanes) to provide 6.95 g (61%) ofthe title compound.

Example 2b6-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Phenol (0.094 g, 0.997 mmol), Example 2a (0.4 g, 0.906 mmol) and cesiumcarbonate (0.325 g, 0.997 mmol) were combined in DMSO (4.53 mL) andheated at 100° C. for 2 hours. The reaction mixture was partitionedbetween ethyl acetate and water and pH was adjusted to pH 7. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.Purification by flash chromatography (silica gel, 0-4% methanol indichloromethane) afforded 0.28 g (84%) of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 3.57 (s, 3H) 6.28-6.34 (m, 1H) 6.98 (d, J=9.12 Hz,1H) 7.16 (d, J=7.54 Hz, 2H) 7.21-7.32 (m, 2H) 7.40-7.49 (m, 3H) 8.22(dd, J=9.12, 2.78 Hz, 1H) 8.32 (d, J=2.78 Hz, 1H) 12.07-12.11 (m, 1H).MS (ESI+) m/z 362 [M+H]⁺

Example 34-(5-amino-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 2b (0.25 g, 0.692 mmol), iron powder (0.193 g, 3.46 mmol), andammonium chloride (0.056 g, 1.038 mmol) were combined in tetrahydrofuran(6 mL), ethanol (6 mL) and water (2 mL). The mixture was heated at 95°C. with vigorous stirring for 1.5 hours. The reaction mixture was cooledto room temperature and filtered through a plug of Celite to removesolids. The plug was rinsed repeatedly with methanol andtetrahydrofuran. The filtrate was concentrated and the residuepartitioned between ethyl acetate and water. The ethyl acetate layer waswashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 1-4% methanolin dichloromethane) to afford 0.21 g (82%) of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 3.43 (s, 3H) 5.07 (s, 2H) 6.22-6.25 (m, 1H) 6.59(dd, J=8.48, 2.71 Hz, 1H) 6.68 (d, J=7.80 Hz, 2H) 6.74 (d, J=2.71 Hz,1H) 6.80-6.88 (m, 2H) 7.11-7.19 (m, 3H) 7.24 (t, J=2.71 Hz, 1H) 11.91(s, 1H). MS (ESI+) m/z 362 [M+H]⁺.

Example 4N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamideMethod A:

To a solution of Example 3 (0.125 g, 0.377 mmol) and triethylamine(0.131 mL, 0.943 mmol) in dichloromethane (3.0 mL) was added dropwisemethanesulfonyl chloride (0.064 mL, 0.830 mmol). The reaction mixturewas stirred for 2 hours at ambient temperature and then concentrated.The residue was dissolved in a mixture of dioxane (5 mL) and 1M sodiumhydroxide (2 mL) and heated for 1 hour at 90° C. The reaction mixturewas cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCland partitioned. The organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0-4% methanol in dichloromethane) to afford0.20 g (77%) of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 3.02 (s,3H) 3.48 (s, 3H) 6.23-6.30 (m, 1H) 6.85 (d, J=7.46 Hz, 2H) 6.99 (t,J=7.29 Hz, 1H) 7.04 (d, J=8.82 Hz, 1H) 7.20-7.29 (m, 5H) 7.39 (d, J=2.71Hz, 1H) 9.72 (s, 1H) 12.01 (s, 1H). MS (ESI+) m/z 410 [M+H]⁺.

Method B:

The product of Example 7d (1.127 g, 2 mmol), potassium hydroxide (1.82g, 52.5 mmol) and cetyltrimethylammonium bromide (0.036 g, 0.100 mmol)were combined in tetrahydrofuran (15.00 mL) and water (5.00 mL) and themixture heated at 100° C. for 14 hours. The reaction mixture waspartitioned between equal volumes of EtOAc and water and the pH wasadjusted to pH 7 by careful addition of concentrated HCl. The organiclayer was separated, washed three times with saturated brine, dried(Na₂SO₄) and concentrated. Purification by trituration indichloromethane afforded the title compound (0.76 g, 93%).

Example 52,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide

To a solution of Example 3 (0.05 g, 0.151 mmol) and triethylamine (0.053mL, 0.377 mmol) in dichloromethane (1.0 mL) was added dropwise2,2,2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol). Thereaction mixture was stirred for 1 hour at room temperature and thenpurified by flash chromatography (silica gel, 0-5% methanol indichloromethane) to afford 0.050 g (68%) of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 3.49 (s, 3H) 4.55 (q, J=9.91 Hz, 2H) 6.28 (t,J=2.38 Hz, 1H) 6.86 (d, J=7.54 Hz, 2H) 6.95-7.07 (m, 2H) 7.20-7.31 (m,5H) 7.40 (d, J=2.78 Hz, 1H) 10.43 (s, 1H) 12.02 (s, 1H). MS (APCI+) m/z478 [M+H]⁺.

Example 6N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]acetamideExample 6a6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 1e (6.55 g, 17.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.73 g,34.4 mmol), potassium acetate (3.71 g, 37.8 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.393 g, 0.430 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 0.819 g,1.72 mmol) were combined and sparged with argon for 1 hour withstirring. Dioxane (86 mL) was sparged with nitrogen for 1 hour,transferred via canula under nitrogen to the solid components, and themixture was heated under argon at 80° C. for 5 hours. The reactionmixture was cooled to room temperature, partitioned between ethylacetate and water, and filtered through Celite. The ethyl acetate layerwas washed twice with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by chromatography (silica gel, 25-80% ethylacetate in hexane). The resulting material from chromatography wastriturated with a minimal amount of hexanes (30 mL) and the particulatesolid was collected by filtration, rinsed with a minimal amount ofhexanes and dried to constant mass to afford the title compound (5.4 g,73%).

Example 6b N-(3-bromo-4-phenoxyphenyl)acetamide

Example 7b (0.2 g, 0.757 mmol), and acetic anhydride (1 mL, 10.60 mmol)were combined in a 5 mL microwave tube, sealed and heated undermicrowave at 100° C. for 30 minutes. The mixture was concentrated andthe residue was purified by chromatography (silica gel, 0-50% ethylacetate in hexanes) to afford the title compound (0.22 g, 95%).

Example 6cN-(3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl)acetamide

Example 6a (0.07 g, 0.163 mmol), Example 6b (0.075 g, 0.245 mmol),tetrakis(triphenylphosphine)palladium(0) (9.44 mg, 8.17 μmol) and sodiumcarbonate (2.0 M, 0.245 mL, 0.490 mmol) were combined in DME (0.817 mL)and water (0.817 mL) in a 5 mL microwave tube, sealed, sparged withnitrogen and heated under microwave at 120° C. for 30 minutes. Themixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.Purification by chromatography (silica gel, 0-5% methanol indichloromethane) afforded the title compound (0.048 g, 56%).

Example 6dN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]acetamide

Example 6c (0.048 g, 0.091 mmol) and potassium carbonate (0.044 g, 0.318mmol) were combined in methanol (2 mL) and water (0.200 mL) in a 2 mLmicrowave tube, sealed, and heated under microwave at 110° C. for 30minutes. The reaction mixture was concentrated and the residuepartitioned between ethyl acetate and water, adjusting the pH to 6 with1M HCl. The organic layer was separated and concentrated. Purificationby flash chromatography (silica gel, 0-4% methanol in dichloromethane)afforded 0.018 g (53%) of the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 2.05 (s, 3H) 3.48 (s, 3H) 6.25-6.30 (m, 1H) 6.80 (d, J=7.46 Hz, 2H)6.96 (t, J=7.29 Hz, 1H) 7.01 (d, J=8.82 Hz, 1H) 7.18-7.31 (m, 4H) 7.56(dd, J=8.65, 2.54 Hz, 1H) 7.79 (d, J=2.71 Hz, 1H) 10.04 (s, 1H) 11.97(s, 1H). MS (ESI+) m/z 374 [M+H]⁺.

Example 7N-(3-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-4-phenoxyphenyl)methanesulfonamideExample 7a 2-bromo-4-nitro-1-phenoxybenzene

2-Bromo-1-fluoro-4-nitrobenzene (2.5 g, 11.4 mmol), phenol (1.28 g, 13.6mmol), and cesium carbonate (4.44 g, 13.6 mmol) were combined indimethylsulfoxide (140 mL) and heated to 110° C. for 1 hour. Thereaction mixture was partitioned between ethyl acetate and brine. Thecombined organics were washed with brine, dried (MgSO₄), filtered andconcentrated to afford the title compound.

Example 7b 3-bromo-4-phenoxyaniline

Example 7a (3.43 g, 11.7 mmol), iron powder (3.26 g, 58.4 mmol), andammonium chloride (1.25 g, 23.4 mmol) were combined in ethanol (50 mL),tetrahydrofuran (50 mL), and water (16.7 mL), and heated at 100° C. for2 hour. The reaction mixture was cooled to just below reflux, vacuumfiltered through diatomaceous earth, the filter cake washed with warmmethanol (3×35 mL), and the filtrate concentrated under reducedpressure. The residue was partitioned between saturated aqueous NaHCO₃and ethyl acetate (3×125 mL). The combined organics were washed withbrine, dried (MgSO₄), gravity filtered then concentrated to afford thetitle compound.

Example 7c N-(3-bromo-4-phenoxyphenyl)methanesulfonamide

Example 7b (2.86 g, 10.8 mmol) and triethylamine (6.03 mL, 43.3 mmol)were stirred in dichloromethane (48.1 mL) at ambient temperature.Methanesulfonyl chloride (2.53 mL, 32.4 mmol) was added dropwise and thesolution stirred at ambient temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, dioxane (24 mL) and sodiumhydroxide (10% w/v, 12 mL, 0.427 mmol) were added, and the solution washeated to 70° C. for 1 h. The solution was neutralized to a pH of 7 withsaturated aqueous NH₄Cl (200 mL). The aqueous phase was extracted withethyl acetate (3×125 mL). The combined organics were washed with brine,dried (MgSO₄), filtered, then concentrated. The residue was purified byflash chromatography (silica gel, 0-25% ethyl acetate/hexane gradient,)to afford the title compound.

Example 7dN-(3-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-4-phenoxyphenyl)methanesulfonamide

Example 6a (0.670 g, 1.564 mmol), Example 7c (0.562 g, 1.643 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.039 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.023 g,0.078 mmol) and potassium phosphate tribasic (1.03 g, 4.85 mmol) werecombined and sparged with argon for 30 minutes. A solution of 4:1dioxane/water (10 mL total volume) was sparged with nitrogen for 30minutes and transferred by syringe into the reaction vessel under argon.The reaction mixture was stirred at 60° C. for 2 hours, cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried (Na₂SO₄), treated with3-mercaptopropyl functionalized silica gel (Aldrich, 538086-100G) for 45minutes, filtered and concentrated. Purification by chromatography(silica gel, 20-100% ethyl acetate in hexanes) afforded 0.68 g (74%) ofthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 2.38 (s, 3H) 3.02 (s,3H) 3.38 (s, 3H) 6.52 (d, J=3.39 Hz, 1H) 6.82 (d, J=7.80 Hz, 2H)6.96-7.04 (m, 2H) 7.19-7.28 (m, 4H) 7.41 (d, J=8.14 Hz, 2H) 7.48 (s, 1H)7.89-7.97 (m, 3H) 9.73 (s, 1H). MS (ESI+) m/z 564 [M+H]⁺.

Example 8N-methyl-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide

A mixture of Example 7d (0.113 g, 0.2 mmol) and potassium carbonate(0.111 g, 0.800 mmol) in methanol (0.9 mL) and water (0.1 mL) was heatedat 100° C. for 1 hour. The reaction was partitioned between ethylacetate and water adjusting the pH to 7. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by reverse phase HPLC (C18, 10-100% CH₃CN/water (0.1% TFA)) toafford the title compound (0.012 g, 14%). ¹H NMR (300 MHz, DMSO-d₆) δ2.99 (s, 3H) 3.27 (s, 3H) 3.51 (s, 3H) 6.27-6.32 (m, 1H) 6.93 (d, J=7.80Hz, 2H) 6.99 (d, J=8.82 Hz, 1H) 7.03-7.10 (m, 1H) 7.25-7.34 (m, 4H) 7.40(dd, J=8.65, 2.88 Hz, 1H) 7.55 (d, J=2.71 Hz, 1H) 12.01 (s, 1H). MS(ESI+) m/z 424 [M+H]⁺.

Example 9 ethyl3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoateExample 9a ethyl4-fluoro-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate

A mixture of Example 1e (1.33 g, 3.5 mmol),5-(ethoxycarbonyl)-2-fluorophenylboronic acid (1.04 g, 4.9 mmol),Pd(PPh₃)₄ (0.20 g, 5 mol %), and sodium carbonate (0.742 g, 7.0 mmol) intoluene (12 mL), ethanol (3 mL) and water (3 mL) was degassed andstirred under a nitrogen atmosphere. The reaction mixture was heated at90° C. for 24 hours. The reaction mixture was cooled to room temperatureand partitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 20-50% ethyl acetate in hexanes) to afford 1.43 g (87%) of thetitle compound.

Example 9b ethyl3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoate

A mixture of Example 9a (1.43 g, 3.05 mmol), phenol (0.0344 g, 3.66mmol) and cesium carbonate (0.995, 3.05 mmol), in DMSO (15 mL) washeated at 110° C. for 12 hours. After cooling to room temperature, thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 30-80% ethyl acetate/hexane) to afford 0.85g (72%) of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.31 (t,J=7.02 Hz, 3H), 3.55 (s, 3H), 4.32 (q, J=7.22 Hz, 2H), 6.23 (t, J=2.29Hz, 1H), 6.97 (d, J=8.54 Hz, 1H), 7.06 (d, J=8.24 Hz, 2H), 7.17 (t,J=7.32 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.36-7.51 (m, 3H), 7.94 (dd,J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.02 (s, 1H). MS (ESI+)m/z 389.2 (M+H)⁺.

Example 103-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoicacid

A mixture of Example 9b (0.23 g, 0.59 mmol) and sodium hydroxide (0.89mL of 2.0 M aqueous solution) in dioxane (10 mL) was heated at 60° C.for 2 hours. The reaction mixture was cooled to room temperature andpoured into water (100 mL). After addition of concentrated HCl (5 mL),the mixture was extracted with ethyl acetate (3×40 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford 0.21 g (98%) of the title compound. ¹H NMR (500MHz, DMSO-d₆) δ 3.55 (s, 3H), 6.24-6.25 (m, 1H), 6.94 (d, J=8.54 Hz,1H), 7.05 (d, J=7.63 Hz, 2H), 7.16 (t, J=7.32 Hz, 1H), 7.27 (t, J=2.9Hz, 1H), 7.35-7.40 (m, 3H), 7.92 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d,J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 361.2 (M+H)⁺.

Example 11N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-3-yloxy)phenyl]methanesulfonamideExample 11a6-methyl-4-(5-nitro-2-(pyridin-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 11a was prepared according to the procedure used for thepreparation of Example 2b, substituting pyridin-3-ol for phenol, toprovide the title compound.

Example 11b4-(5-amino-2-(pyridin-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 11b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 11a for Example 2b, toprovide the title compound.

Example 11cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-3-yloxy)phenyl]methanesulfonamide

Example 11c was prepared according to the procedure used in method A ofExample 4, substituting Example 11b for Example 3, and purified byPreparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) toprovide the TFA salt of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.49 (s, 3H), 3.05 (s, 3H), 6.25 (dd, J=2.8, 1.9 Hz, 1H), 7.16 (d, J=8.7Hz, 1H), 7.34-7.21 (m, 5H), 7.40 (d, J=2.6 Hz, 1H), 8.23-8.16 (m, 2H),9.80 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 411.1 (M+H)⁺.

Example 126-methyl-4-[2-(morpholin-4-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 12 was prepared according to the procedure used for thepreparation of Example 1f, substituting2-(morpholinomethyl)phenylboronic acid for 2-phenoxyphenylboronic acid,followed by purification by preparative HPLC (C18, 10-100% acetonitrilein 0.1% TFA in water), to provide the TFA salt of the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ 2.85 (br, 2H), 3.09 (br, 2H), 3.56 (s, 3H),3.74 (br, 2H), 4.26 (br, 2H), 5.89-5.90 (m, 1H), 7.20 (s, 1H), 7.29 (t,J=2.75 Hz, 1H), 7.39-7.43 (m, 1H), 7.53-7.55 (m, 2H), 7.75-7.77 (m, 1H),9.73 (br, 1H), 12.12 (s, 1H). MS (ESI+) m/z 324.0 (M+H)⁺.

Example 13N-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamideExample 13a3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoylchloride

A solution of Example 10 (0.24 g, 0.67 mmol) in dichloromethane (10 mL)was treated with oxalyl chloride (0.17 g, 1.33 mmol) anddimethylformamide (5 mg, 10 mol %). The reaction mixture was stirred atroom temperature for 2 hours. The solvent was removed under reducedpressure to afford the title compound (0.25 g, quantitative).

Example 13bN-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide

A solution of Example 13a (0.040 g, 0.11 mmol) in tetrahydrofuran (1 mL)was treated with ethylamine (0.21 mL of a 2 M solution intetrahydrofuran, 0.42 mmol) for 2 h. The reaction mixture wasconcentrated and the residue purified by preparative HPLC (C18, 10-90%acetonitrile in 0.1% TFA in water) to afford the title compound (0.025g, 61%). ¹H NMR (500 MHz, DMSO-d₆) δ 1.12 (t, J=7.32 Hz, 3H), 3.25-3.32(m, 2H), 3.54 (s, 3H), 6.23-6.24 (m, 1H), 6.95-6.99 (m, 3H), 7.11 (t,J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.31-7.37 (m, 3H), 7.84 (dd,J=8.54, 2.44 Hz, 1H), 7.98 (d, J=2.44 Hz, 1H), 8.46 (t, J=5.49 Hz, 1H),11.99 (s, 1H). MS (ESI+) m/z 388.2 (M+H)⁺.

Example 143-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(tetrahydrofuran-2-ylmethyl)benzamide

Example 14 was prepared according to the procedure used for thepreparation of Example 13b, substituting(tetrahydrofuran-2-yl)methanamine for ethylamine, and dichloromethanefor tetrahydrofuran, respectively, to provide the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ 1.56-1.57 (m, 1H), 1.79-1.89 (m, 3H), 3.26-3.32 (m,3H), 3.53 (s, 3H), 3.58-3.63 (m, 1H), 3.73-3.78 (m, 1H), 3.94-3.97 (m,1H), 6.21-6.22 (m, 1H), 6.93-6.98 (m, 3H), 7.10 (t, J=7.48 Hz, 1H), 7.25(t, J=2.9 Hz, 1H), 7.30-7.35 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz, 1H),7.98 (d, J=2.14 Hz, 1H), 8.52 (t, J=5.8 Hz, 1H), 12.00 (s, 1H). MS(ESI+) m/z 444.2 (M+H)⁺.

Example 15N-cyclopentyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide

Example 15 was prepared according to the procedure used for thepreparation of Example 13b, substituting cyclopentylamine forethylamine, and dichloromethane for tetrahydrofuran, respectively, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.49-1.66 (m,4H), 1.65-1.69 (m, 2H), 1.85-1.91 (m, 2H), 3.54 (s, 3H), 4.20-4.26 (m,1H), 6.20-6.22 (m, 1H), 6.95-6.98 (m, 3H), 7.01 (t, J=7.32 Hz, 1H), 7.26(t, J=2.75 Hz, 1H), 7.30-7.36 (m, 3H), 7.85 (dd, J=8.54, 2.14 Hz, 1H),7.99 (d, J=2.44 Hz, 1H), 8.52 (t, J=5.8 Hz, 1H), 12.01 (s, 1H). MS(ESI+) m/z 428.3 (M+H)⁺.

Example 16N-(2,2-difluoroethyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide

Example 16 was prepared according to the procedure used for thepreparation of Example 13b, substituting 2,2-difluoroethanamine forethylamine, and dichloromethane for tetrahydrofuran, respectively, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.55 (s, 3H),3.62-3.72 (m, 3H), 5.97 (t, J=3.97 Hz, 0.25H), 6.11 (t, J=4.12 Hz,0.5H), 6.23-6.26 (m, 1.25H), 6.98 (d, J=8.54 Hz, 1H), 7.01 (d, J=7.63Hz, 2H), 7.13 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.33-7.36 (m,3H), 7.88 (dd, J=8.54, 2.44 Hz, 1H), 8.03 (d, J=2.14 Hz, 1H), 8.85 (t,J=5.8 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 424.2 (M+H)⁺.

Example 173-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(1,3-thiazol-2-yl)benzamide

Example 17 was prepared according to the procedure used for thepreparation of Example 13b, substituting thiazol-2-amine for ethylamine,and dichloromethane for tetrahydrofuran, respectively, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.58 (s, 3H), 6.30-6.31 (m,1H), 6.23-6.26 (m, 1H), 6.98 (d, J=8.54 Hz, 1H), 7.07 (d, J=7.63 Hz,2H), 7.17 (t, J=7.32 Hz, 1H), 7.27-7.29 (m, 2H), 7.38-7.42 (m, 3H), 7.56(d, J=3.36 Hz, 1H), 8.09 (dd, J=8.55, 2.44 Hz, 1H), 8.28 (d, J=2.44 Hz,1H), 12.04 (s, 1H), 12.61 (s, 1H). MS (ESI+) m/z 443.1 (M+H)⁺.

Example 18N-(1,1-dioxidotetrahydrothiophen-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide

Example 18 was prepared according to the procedure used for thepreparation of Example 13b, substituting1,1-dioxidotetrahydrothien-3-ylamine for ethylamine, and dichloromethanefor tetrahydrofuran, respectively, to provide the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ 2.20-2.23 (m, 1H), 2.41-2.45 (m, 1H), 3.04-3.09 (m,1H), 3.19-3.23 (m, 1H), 3.34-3.37 (m, 1H), 3.48-3.53 (m, 1H), 3.55 (s,3H), 4.66-4.76 (m, 1H), 6.30-6.31 (m, 1H), 6.21-6.22 (m, 1H), 6.99 (dd,J=8.09, 2.59 Hz, 2H), 7.12 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H),7.31-7.37 (m, 3H), 7.87 (dd, J=8.54, 2.14 Hz, 1H), 8.02 (d, J=2.14 Hz,1H), 8.72 (d, J=7.02 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 478.2 (M+H)⁺.

Example 193-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide

Example 19 was prepared according to the procedure used for thepreparation of Example 13b, substituting aqueous ammonium hydroxide forethylamine to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ3.54 (s, 3H), 6.23-6.24 (m, 1H), 6.94 (d, J=8.54 Hz, 1H), 6.98-7.00 (m,2H), 7.11 (t, J=7.48 Hz, 1H), 7.26 (t, J=2.75 Hz, 1H), 7.31-7.37 (m,4H), 7.86 (dd, J=8.54, 2.44 Hz, 1H), 7.96 (s, 1H), 8.02 (d, J=2.44 Hz,1H), 12.01 (s, 1H). MS (ESI+) m/z 360.2 (M+H)⁺.

Example 204-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 20a ethyl3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoate

Example 20a was prepared according to the procedure used for thepreparation of Example 1c, substituting Example 9b for Example 1b toprovide the title compound.

Example 20b4-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 20a (0.32 g, 0.59 mmol) in tetrahydrofuran (5 mL) was cooled to0° C. To this solution was added 1.0 N aluminum lithium hydride (0.59mL, 0.59 mmol). The reaction mixture was stirred at room temperature for1 hour. The reaction mixture was quenched with 2.0 N HCl (5 mL), andthen partitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel eluting with 50-100% ethyl acetate in hexanes to afford 0.08 g (39%)of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.49 (s, 3H), 4.54(d, J=5.49 Hz, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.23-6.24 (m, 1H), 6.94 (d,J=7.93 Hz, 2H), 6.97-7.01 (m, 2H), 7.22-7.28 (m, 4H), 7.32 (dd, J=8.39,2.29 Hz, 1H), 7.16 (d, J=1.83 Hz, 1H), 11.97 (s, 1H). MS (ESI+) m/z347.3 (M+H)⁺.

Example 21N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide

Example 21 was prepared according to the procedure used in method A ofExample 4, substituting ethanesulfonyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.24 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.3 Hz, 2H), 3.48 (s, 3H), 6.26 (t,J=2.3 Hz, 1H), 6.88-6.80 (m, 2H), 7.07-6.95 (m, 2H), 7.31-7.18 (m, 5H),7.40 (d, J=2.7 Hz, 1H), 9.79 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z424.2 (M+H)⁺.

Example 22N,N-dimethyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]sulfuricdiamide

Example 22 was prepared according to the procedure used in method A ofExample 4, substituting dimethylsulfamoyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ2.74 (s, 6H), 3.48 (s, 3H), 6.28-6.23 (m, 1H), 6.85-6.78 (m, 2H),7.06-6.93 (m, 2H), 7.31-7.17 (m, 5H), 7.40 (d, J=2.7 Hz, 1H), 9.91 (s,1H), 12.04-12.00 (m, 1H). MS (ESI+) m/z 439.1 (M+H)⁺.

Example 23N-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxypyridin-3-yl]methanesulfonamideExample 23a 3-bromo-5-nitro-2-phenoxypyridine

Phenol (0.416 g, 4.42 mmol), 3-bromo-2-chloro-5-nitropyridine(Combi-Blocks, CAS [5470-17-7], 1 g, 4.21 mmol) and cesium carbonate(1.372 g, 4.21 mmol) were combined in DMSO (8 mL) and heated at 80° C.for 30 minutes. The reaction mixture was cooled and partitioned betweenethyl acetate and water. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. Purification of the residue bychromatography (silica gel, 0-30% ethyl acetate in hexanes) afforded thetitle compound (1.13 g, 91%).

Example 23b6-methyl-4-(5-nitro-2-phenoxypyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 23b was prepared according to the procedure used for thepreparation of Example 7d, substituting the product of Example 23a forthe product of Example 7c and stirring at 60° C. for 24 hours, toprovide the title compound.

Example 23c4-(5-amino-2-phenoxypyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 23c was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 23b forthe product of Example 2, to provide the title compound.

Example 23dN-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxypyridin-3-yl]methanesulfonamide

Example 23d was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 23c for the product ofExample 3, to provide the title compound (0.035 g, 36%). ¹H NMR (300MHz, DMSO-d₆) δ 3.05 (s, 3H) 3.57 (s, 3H) 6.28-6.36 (m, 1H) 7.10 (d,J=7.54 Hz, 2H) 7.16 (t, J=7.54 Hz, 1H) 7.28-7.41 (m, 3H) 7.48 (s, 1H)7.78 (d, J=2.78 Hz, 1H) 7.96 (d, J=2.38 Hz, 1H) 9.79 (s, 1H) 12.11 (s,1H). MS (ESI+) m/z 411.0 (M+H)⁺.

Example 24N-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamideExample 24a4-(2,3-difluoro-5-nitrophenyl)-6-methyl-1-tosyl-H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 24a was prepared according to the procedure used for thepreparation of Example 7d, substituting1-bromo-2,3-difluoro-5-nitrobenzene (Oakwood Products) for the productof Example 7c, to provide the title compound.

Example 24b4-(3-fluoro-5-nitro-2-phenoxyphenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Phenol (0.043 g, 0.457 mmol), Example 24a (0.2 g, 0.435 mmol) and cesiumcarbonate (0.142 g, 0.435 mmol) were combined in DMSO (2.177 mL) andheated at 80° C. for 30 minutes. The reaction mix was cooled andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (Na₂SO₄), filtered and concentrated to affordthe title compound.

Example 24c4-(5-amino-3-fluoro-2-phenoxyphenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 24c was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 24b forthe product of Example 2, to provide the title compound.

Example 24dN-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide

Example 24d was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 24c for the product ofExample 3, to provide the title compound (0.13 g, 67%). ¹H NMR (300 MHz,DMSO-d₆) δ 3.05 (s, 3H) 3.57 (s, 3H) 6.28-6.36 (m, 1H) 7.10 (d, J=7.54Hz, 2H) 7.16 (t, J=7.54 Hz, 1H) 7.28-7.41 (m, 3H) 7.48 (s, 1H) 7.78 (d,J=2.78 Hz, 1H) 7.96 (d, J=2.38 Hz, 1H) 9.79 (s, 1H) 12.11 (s, 1H).

Example 25N-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 25a2-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)benzonitrile

Example 25a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2-hydroxybenzonitrile forphenol, to provide the title compound.

Example 25b2-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)benzonitrile

Example 25b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 25a forthe product of Example 2b, to provide the title compound.

Example 25cN-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 25c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 25b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.07 (s, 3H), 3.50 (s, 3H), 6.26 (dd, J=2.8, 1.9 Hz, 1H), 6.73 (dd,J=8.6, 0.9 Hz, 1H), 7.07 (td, J=7.6, 0.9 Hz, 1H), 7.34-7.23 (m, 4H),7.53-7.40 (m, 2H), 7.71 (dd, J=7.7, 1.7 Hz, 1H), 9.89 (s, 1H), 12.03(bs, 1H). MS (ESI+) m/z 435.2 (M+H)⁺.

Example 26N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 26a4-(2-(4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 26a was prepared according to the procedure used for thepreparation of Example 2b, substituting 4-fluorophenol for phenol, toprovide the title compound.

Example 26b4-(5-amino-2-(4-fluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 26b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 26a forthe product of Example 2b, to provide the title compound.

Example 26cN-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 26c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 26b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.02 (s, 3H), 3.50 (s, 3H), 6.29-6.23 (m, 1H), 6.94-6.82 (m, 2H),7.14-6.96 (m, 3H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 7.31-7.24 (m, 2H), 7.38(d, J=2.7 Hz, 1H), 9.71 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 428.1(M+H)⁺.

Example 27N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 27a4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 27a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2,4-difluorophenol for phenol,to provide the title compound.

Example 27b4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 27b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 27a forthe product of Example 2b, to provide the title compound.

Example 27cN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 27b (50 mg, 0.136 mmol) and triethylamine (0.057 mL, 0.408 mmol)were combined in CH₂C₁₂ (9 mL). Methanesulfonyl chloride (0.042 mL,0.544 mmol) was added dropwise and the solution stirred at ambienttemperature for 1 hour. The solution was concentrated under reducedpressure, dioxane (5 mL) and sodium hydroxide (10% w/v, 3 mL, 0.136mmol) were added and the solution heated at 70° C. for 1 hour. Themixture was cooled to ambient temperature and then neutralized withsaturated NH₄Cl (100 mL) to a pH of 8. The organic layer was separatedand the aqueous phase was extracted with ethyl acetate (3×25 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated. Purification by reverse phase HPLC (C18, 10-100%acetonitrile/water, 0.1% TFA) afforded 27.5 mg (45.4%) of the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ 3.01 (s, 3H), 3.53 (s, 3H),6.29-6.23 (m, 1H), 7.04-6.90 (m, 2H), 7.09 (td, J=9.1, 5.6 Hz, 1H),7.44-7.14 (m, 5H), 9.70 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 446.1(M+H)⁺.

Example 28N-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamideExample 28a4-(3-chloro-2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 28a was prepared according to the procedure used for thepreparation of Example 6c, substituting1,3-dichloro-2-fluoro-5-nitrobenzene (0.176 g, 0.841 mmol) for theproduct of Example 6b, to provide the title compound.

Example 28bN-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide

Example 28b was prepared according to the procedures used for thepreparation of Examples 24b-24d, substituting Example 28a for theproduct of Example 24a, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 3.12 (s, 3H) 3.43 (s, 3H) 6.25-6.29 (m, 1H) 6.63 (d, J=7.93Hz, 2H) 6.87 (t, J=7.34 Hz, 1H) 7.10-7.18 (m, 2H) 7.27-7.31 (m, 2H) 7.39(s, 2H) 10.05 (s, 1H) 12.04 (s, 1H). MS (ESI+) m/z 444 (M+H)⁺.

Example 29N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]methanesulfonamideExample 29a6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Tetrahydro-2H-pyran-4-ol (0.046 g, 0.453 mmol) in tetrahydrofuran (2 mL)was treated with sodium hydride (0.022 g, 0.906 mmol, 0.036 g of 60%dispersion in oil) at room temperature. The reaction mixture was stirredfor 10 minutes. To this solution was added Example 2a (0.1 g. 0.227mmol). The reaction mixture was heated at 50° C. for 2 hours. Aftercooling to room temperature, the reaction mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted twicewith additional ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate to afford 0.055 g of the title compound.

Example 29b4-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 29b (0.055 g) and 10% palladium on carbon (0.050 g)in ethyl acetate (10 mL) was treated with a balloon of hydrogenovernight. The solid was removed by filtration. The filtrate wasconcentrated under reduced pressure to provide 0.042 g of the titlecompound.

Example 29cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]methanesulfonamide

Example 29c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 29b for the product ofExample 3, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ1.45-1.51 (m, 2H), 1.82-1.87 (m, 2H), 2.94 (s, 3H), 3.35-3.41 (m, 2),3.56 (s, 3H), 3.60-3.68 (m, 2H), 4.45-4.49 (m, 1H), 6.20 (t, J=2.29 Hz,1H), 7.14-7.16 (m, 2H), 7.28-7.29 (m, 3H), 9.45 (s, 1H), 12.01 (s, 1H).(ESI+) m/z 418.2 (M+H)⁺.

Example 306-methyl-4-[2-phenoxy-5-(1H-pyrazol-1-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 20b (0.04 g, 0.115 mmol), 1H-pyrazole (0.016 g,0.231 mmol), and triphenylphosphine (0.061 g, 0.231 mmol) intetrahydrofuran (1 mL) was stirred for 2 minutes. To this solution wasadded di-t-butyl azodicarboxylate (DTBAD, 0.053 g, 0.231 mmol). Thereaction mixture was stirred at room temperature for 3 hours. Thesolvent was removed under reduced pressure, and the residue was purifiedby preparative HPLC (C18, 10-80% acetonitrile/water with 0.1% TFA) toafford 0.006 g of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.49(s, 3H), 5.37 (s, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.17-6.18 (m, 1H), 6.28(t, J=1.98 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 6.97 (d, J=8.24 Hz, 1H),7.02 (t, J=7.32 Hz, 4H), 7.22-7.29 (m, 5H), 7.39 (d, J=2.14 Hz, 1H),7.47 (d, J=1.83 Hz, 1H), 7.53-7.46 (m, 3H), 7.86 (d, J=2.44 Hz, 1H),11.97 (s, 1H). (ESI+) m/z 397.2 (M+H)⁺.

Example 31N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]methanesulfonamideExample 31a6-methyl-4-(5-nitro-2-(tetrahydrofuran-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 31a was prepared according to the procedure used for thepreparation of Example 29a, substituting tetrahydrofuran-3-ol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 31b4-(5-amino-2-(tetrahydrofuran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 31b was prepared according to the procedure used for thepreparation of Example 29b, substituting the product of Example 31a forthe product of Example 29a, to provide the title compound.

Example 31cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]methanesulfonamide

Example 31 was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 31b for the product ofExample 3, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ1.84-1.90 (m, 1H), 2.08-2.17 (m, 1H), 2.95 (s, 3H), 3.35-3.41 (m, 2),3.56 (s, 3H), 3.62-3.69 (M, 2H), 3.80-3.84 (m, 1H), 4.96-4.98 (m, 1H),6.17-6.18 (m, 1H), 7.06-7.08 (m, 1H), 7.16-7.18 (m, 1H), 7.25 (s, 1H),7.27-7.29 (m, 2H), 9.45 (s, 1H), 12.00 (s, 1H). (ESI+) m/z 404.2 (M+H)⁺.

Example 32N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(trifluoromethyl)phenoxy]phenyl}methanesulfonamideExample 32a6-methyl-4-(5-nitro-2-(2-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 32a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2-(trifluoromethyl)phenol forphenol, to provide the title compound.

Example 32b4-(5-amino-2-(2-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 32b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 32a forthe product of Example 2b, to provide the title compound.

Example 32cN-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(trifluoromethyl)phenoxy]phenyl}methanesulfonamide

Example 32c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 32b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.05 (s, 3H), 3.44 (s, 3H), 6.32-6.26 (m, 1H), 6.75 (d, J=8.4 Hz, 1H),7.17-7.07 (m, 2H), 7.34-7.18 (m, 3H), 7.53-7.38 (m, 2H), 7.65 (dd,J=7.8, 1.6 Hz, 1H), 9.84 (s, 1H), 12.09-11.99 (m, 1H). MS (ESI+) m/z478.1 (M+H)⁺.

Example 33N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 33a4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)benzonitrile

Example 33a was prepared according to the procedure used for thepreparation of Example 2b, substituting 4-hydroxybenzonitrile forphenol, to provide the title compound.

Example 33b4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)benzonitrile

Example 33b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 33a forthe product of Example 2b, to provide the title compound.

Example 33cN-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 33c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 33b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.07 (s, 3H), 3.46 (s, 3H), 6.27-6.21 (m, 1H), 6.94-6.87 (m, 2H),7.32-7.20 (m, 4H), 7.42 (d, J=2.5 Hz, 1H), 7.70-7.63 (m, 2H), 9.87 (s,1H), 12.03 (bs, 1H). MS (ESI+) m/z 435.2 (M+H)⁺.

Example 34N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 34a4-(2-(2-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 34a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2-chloro-4-fluorophenol forphenol, to provide the title compound.

Example 34b4-(5-amino-2-(2-chloro-4-fluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 34b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 34a forthe product of Example 2b, to provide the title compound.

Example 34cN-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 34c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 34b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.02 (s, 3H), 3.52 (s, 3H), 6.29 (t, J=2.3 Hz, 1H), 6.99-6.88 (m, 2H),7.14-7.03 (m, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 7.28 (t, J=2.8 Hz, 1H),7.34 (s, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.49 (dd, J=8.3, 3.0 Hz, 1H), 9.75(s, 1H), 12.05 (bs, 1H). MS (ESI+) m/z 462.1 (M+H)⁺.

Example 35[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]aceticacid Example 35a ethyl 2-(3-bromo-4-hydroxyphenyl)acetate

To a solution of ethyl 2-(4-hydroxyphenyl)acetate (Alfa, 2.70 g, 15mmol) in acetic acid (20 mL) was added drop wise over 15 minutes asolution of bromine (0.773 mL, 15.00 mmol) in acetic acid (15 mL). Themixture was stirred at ambient temperature for 30 minutes andevaporated. Purification by chromatography (silica gel, 10-20% ethylacetate in hexane) afforded the title compound (3.66 g, 94%).

Example 35b ethyl 2-(4-(benzyloxy)-3-bromophenyl)acetate

A solution of Example 35a (2.011 mL, 16.90 mmol), and potassiumcarbonate (5.84 g, 42.3 mmol) in ethanol (100 mL) was refluxed for 2hours, cooled, concentrated and the residue was partitioned with ethylacetate and water. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. Purification of the residue bychromatography (silica gel, 0-20% ethyl acetate in hexane) afforded thetitle compound (4.84 g, 98%).

Example 35c ethyl2-(4-(benzyloxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetate

Example 35c was prepared according to the procedure used for thepreparation of Example 7d, substituting the product of Example 35b forthe product of Example 7c to provide the title compound.

Example 35d[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]aceticacid

Example 35c (0.4 g, 0.701 mmol), potassium hydroxide (0.787 g, 14.02mmol) and cetyltrimethylammonium bromide (0.013 g, 0.035 mmol) werecombined in dioxane (10 mL) and water (5 mL) and heated at 100° C. for 3hours, cooled and partitioned between equal volumes of ethyl acetate andwater (20 mL each). The pH was adjusted to pH 2 by careful addition ofconcentrated HCl. The organic layer was separated and washed withsaturated brine, dried (Na₂SO₄), filtered and concentrated. Triturationof the residue in hexane afforded the title compound (0.27 g, 98%). ¹HNMR (300 MHz, DMSO-d₆) δ 3.52 (s, 3H) 3.55 (s, 2H) 5.09 (s, 2H)6.14-6.21 (m, 1H) 7.10-7.33 (m, 10H) 11.97 (s, 1H) 12.25 (s, 1H). MS(ESI+) m/z 389.0 (M+H)⁺.

Example 36N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 36a 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

A mixture of 2-bromo-1-fluoro-4-nitrobenzene (15 g, 68 mmol),2,4-difluorophenol (7.82 ml, 82 mmol), and cesium carbonate (26.7 g, 82mmol) in dimethylsulfoxide (75 mL) was heated to 110° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and water (1000 mL)and saturated aqueous sodium chloride (1000 mL) were added. The mixturewas extracted with ethyl acetate (3×200 mL). The combined organics werewashed with saturated aqueous sodium chloride, dried (anhydrousmagnesium sulfate), filtered, and concentrated under reduced pressure toprovide the title compound (22.5 g, quantitative).

Example 36b 3-bromo-4-(2,4-difluorophenoxy)aniline

A mixture of Example 36a (22.5 g, 68.2 mmol), iron powder (19.04 g, 341mmol), and ammonium chloride (7.30 g, 136 mmol) in tetrahydrofuran (117mL), ethanol (117 mL), and water (39.0 mL) was heated under reflux at100° C. for 2 hours. The reaction mixture was cooled to just belowreflux temperature, filtered through celite, and the filter cake washedwith warm methanol (3×50 mL). The resulting solution was concentratedunder reduced pressure and then neutralized to a pH of 8 with saturatedsodium hydrogen carbonate (150 mL). The mixture was extracted with ethylacetate (3×100 mL). The combined organics were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, ethyl acetate/hexane gradient 0-15%) toprovide the title compound (16.8 g, 82% yield).

Example 36c4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 6a (5.0 g, 11.67 mmol), Example 36b (3.85 g, 12.84mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.399 g, 1.366 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.321g, 0.350 mmol), and potassium phosphate (6.19 g, 29.2 mmol) in dioxane(50 mL) and water (12.5 mL) was degassed and back-filled with nitrogenseveral times. The reaction mixture was heated at 60° C. for 16 hoursand then cooled to ambient temperature. The reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate three times. The combinedorganic layers were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashcolumn chromatography (silica gel, 60% ethyl acetate/hexanes) to providethe title compound (4.40 g, 72.3% yield)

Example 36dN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide

A solution of Example 36c (4.35 g, 8.34 mmol) in dichloromethane (50 mL)was cooled to 0° C. To this solution was added ethanesulfonyl chloride(2.37 mL, 25.0 mmol). The reaction mixture was stirred at roomtemperature for 2 hours. The solvent was evaporated, and the residue waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 80% ethyl acetate/hexanes)to provide the title compound (5.34 g, 91% yield).

Example 36eN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

A mixture of Example 36d (5.3 g, 7.5 mmol), potassium hydroxide (8.43 g,150 mmol), and N,N,N-trimethylhexadecan-1-aminium bromide (0.137 g,0.375 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was heated at90° C. for 16 hours. Tetrahydrofuran was removed under reduced pressure,and the residue was partitioned between water and ethyl acetate. Theaqueous layer was neutalized to pH=7 using 10% HCl. The aqueous layerwas then extracted with ethyl acetate. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, ethyl acetate). The desiredfractions were combined and concentrated. The residue was trituratedwith 20 mL of acetonitrile to provide the title compound (2.82 g, 82%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7.3 Hz, 3H), 3.11 (q,J=7.3 Hz, 2H), 3.53 (s, 3H), 6.27-6.22 (m, 1H), 6.91 (d, J=8.7 Hz, 1H),7.13-6.93 (m, 2H), 7.19 (dd, J=8.8, 2.7 Hz, 1H), 7.32-7.25 (m, 2H),7.42-7.31 (m, 2H), 9.77 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 460.1(M+H)⁺.

Example 37N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetamide

Example 27b (50 mg, 0.136 mmol) and triethylamine (56.9 μL, 0.408 mmol)were combined in CH₂Cl₂ (10 mL). Acetyl chloride (11.6 μL, 0.163 mmol)was added dropwise and the solution stirred for 1 hour at ambienttemperature. Water (25 mL) and saturated aqueous sodium bicarbonate (25mL) were added, and the mixture was extracted with CH₂Cl₂ (3×25 mL). Thecombined organics were washed with brine, dried (MgSO₄), filtered, andconcentrated. Purification of the residue by reverse phase HPLC (C18,10-100% acetonitrile/water, 0.1% TFA) afforded 15 mg (28%) of the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ 2.04 (s, 3H), 3.52 (s, 3H),6.29-6.23 (m, 1H), 7.08-6.85 (m, 3H), 7.39-7.25 (m, 3H), 7.53 (dd,J=8.8, 2.6 Hz, 1H), 7.77 (d, J=2.6 Hz, 1H), 10.00 (s, 1H), 12.07-11.96(m, 1H). MS (ESI+) m/z 410.3 (M+H)⁺.

Example 38N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-3,3,3-trifluoropropanamide

Example 38 was prepared according to the procedure used for thepreparation of Example 37, substituting 3,3,3-trifluoropropanoylchloride for acetyl chloride, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 3.54-3.46 (m, 2H), 3.53 (s, 3H), 6.27 (t, J=2.3 Hz, 1H),7.14-6.87 (m, 3H), 7.28 (t, J=2.7 Hz, 1H), 7.31 (s, 1H), 7.37 (ddd,J=11.3, 8.7, 2.8 Hz, 1H), 7.50 (dd, J=8.8, 2.6 Hz, 1H), 7.76 (d, J=2.6Hz, 1H), 10.38 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 478.2 (M+H)⁺.

Example 39N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2,2-dimethylpropanamide

Example 39 was prepared according to the procedure used for thepreparation of Example 37, substituting pivaloyl chloride for acetylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.22 (s, 9H), 3.53 (s, 3H), 6.31-6.25 (m, 1H), 6.88 (d, J=8.8 Hz, 1H),7.08-6.92 (m, 2H), 7.31-7.24 (m, 2H), 7.40-7.29 (m, 1H), 7.62 (dd,J=8.8, 2.6 Hz, 1H), 7.83 (d, J=2.6 Hz, 1H), 9.28 (s, 1H), 12.00 (bs,1H). MS (ESI+) m/z 452.3 (M+H)⁺.

Example 40 ethyl4-(cyclopentylamino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate

A mixture of Example 9a (0.094 g, 0.2 mmol), cyclopentanamine (0.034 g,0.4 mmol), and triethylamine (0.081 g, 0.8 mmol) in DMSO (2 mL) washeated at 120° C. overnight. The reaction mixture was purified bypreparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water to afford0.019 g of the title product. ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t,J=7.02 Hz, 3H), 1.32-1.36 (m, 2H), 1.47-1.55 (m, 3H), 1.88-1.93 (m, 2H),3.55 (s, 3H), 3.83-3.88 (m, 1H), 4.22 (q, J=7.02 Hz, 2H), 5.94 (t,J=2.29 Hz, 1H), 6.77 (d, J=8.85 Hz, 1H), 7.22 (s, 1H), 7.28 (t, J=2.75Hz, 1H), 7.63 (d, J=1.83 Hz, 1H), 7.82 (dd, J=8.54, 2.14, 1H), 12.01 (s,1H). MS (ESI+) m/z 380.2 (M+H)⁺.

Example 414-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 41a4-(5-(hydroxymethyl)-2-phenoxyphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 41a was isolated as a by-product from the preparation of Example20b.

Example 41b3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzylmethanesulfonate

A mixture of Example 41a (0.15 g, 0.3 mmol), methanesulfonyl chloride(0.069 g, 0.6 mmol), and triethylamine (0.121 g, 1.2 mmol) indichloromethane (5 mL) was stirred at room temperature for 2 hours. Thesolvent was removed, and the residue was purified by flashchromatography on silica gel eluting with 20-40% ethyl acetate inhexanes to afford 0.105 g of the title product.

Example 41c4-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

1,2-thiazolidine 1,1-dioxide (0.031 g, 0.259 mmol) in dimethylformamide(1 mL) was treated with 60% sodium hydride (0.012 g, 0.518 mmol, 0.021 gof a 60% in oil dispersion). The reaction mixture was stirred for 5 min.To this solution was added Example 41b (0.05 g, 0.086 mmol). Thereaction mixture was stirred at room temperature for 2 hours. 2 N NaOH(1 mL) was added and the reaction mixture was heated at 65° C. for 2hours. After cooling to room temperature, the reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by preparative HPLC (C18, 10-80%acetonitrile in 0.1% TFA water) to afford 0.025 g (64%) of the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 2.21-2.25 (m, 2H), 3.15 (t, J=6.97Hz, 2H), 3.23-3.27 (m, 2H), 3.50 (s, 3H), 4.13 (s, 2H), 6.25-6.26 (m,1H), 6.88 (d, J=7.63 Hz, 2H), 7.00 (d, J=8.54 Hz, 1H), 7.03-7.05 (m,1H), 7.25-7.30 (m, 4H), 7.34 (dd, J=8.39, 2.29, 1H), 7.48 (d, J=2.44 Hz,1H), 12.00 (s, 1H). MS (ESI+) m/z 450.2 (M+H)⁺.

Example 424-{[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzyl]amino}-4-oxobutanoicacid

Example 42 was prepared according to the procedure used for thepreparation of Example 41c, substituting pyrrolidine-2,5-dione for1,2-thiazolidine 1,1-dioxide, to provide the title compound. ¹H NMR (500MHz, DMSO-d₆) δ 2.37-2.40 (m, 2H), 2.44-2.48 (m, 2H), 3.50 (s, 3H), 4.31(d, J=5.8 Hz, 2H), 6.23-6.24 (m, 1H), 6.84 (d, J=7.63 Hz, 2H), 6.96 (d,J=8.24 Hz, 1H), 7.00 (t, J=7.32 Hz, 1H), 7.22-7.29 (m, 5H), 7.40 (d,J=2.14, 1H), 8.40 (t, J=5.95 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z 446.1(M+H)⁺.

Example 434-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 43a3-chloro-N-(3-chloropropylsulfonyl)-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)propane-1-sulfonamide

A mixture of Example 27b (0.1 g, 0.272 mmol), 3-chloropropane-1-sulfonylchloride (0.145 g, 0.817 mmol), and triethylamine (0.165 g, 1.633 mmol)in dichloromethane (3 mL) was stirred for 2 hours. The solvent wasremoved, and the residue was used directly for the next reaction.

Example 43b4-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Sodium (0.064 g, 2.78 mmol) was dissolved in ethanol (15 mL). To thissolution was added Example 43a (0.18 g, 0.278 mmol) in ethanol (5 mL).The reaction mixture was heated at 75° C. for 2 hours. After cooling,the solvent was removed under reduced pressure, and the residue waspurified by preparative HPLC (C18, 10-80% acetonitrile in 0.1%TFA/water) to afford 0.055 g of the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ 2.37-2.44 (m, 2H), 3.49-3.53 (m, 2H), 3.54 (s, 3H), 3.76 (t,J=6.56 Hz, 2H), 6.27-6.28 (m, 1H), 6.95 (d, J=8.85 Hz, 1H), 7.00-7.12(m, 2H), 7.20 (dd, J=8.85, 2.75 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.32(s, 1H), 7.35-7.41 (m, 2H), 12.05 (s, 1H). MS (ESI+) m/z 472.2 (M+H)⁺.

Example 444-[2-(benzyloxy)-5-(2-hydroxyethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 35d (0.039 g, 0.1 mmol) in tetrahydrofuran (2 mL) was treateddropwise with borane-tetrahydrofuran complex (1M, 0.200 mL, 0.200 mmol),and the mixture was stirred at 40° C. for 1 hour, diluted with 5 mL ofmethanol, heated at 50° C. for 30 minutes and concentrated. Purificationby chromatography (silica gel, 0.5-4% methanol in dichloromethane)afforded the title compound (0.03 g, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ2.70 (t, J=6.94 Hz, 2H) 3.52 (s, 3H) 3.57-3.64 (m, 2H) 4.59-4.63 (m, 1H)5.06 (s, 2H) 6.14-6.18 (m, 1H) 7.08-7.18 (m, 2H) 7.20-7.32 (m, 8H) 11.95(s, 1H). MS (ESI+) m/z 375.0 (M+H)⁺.

Example 45 methyl[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetateExample 45a2-(4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetylchloride

Example 35d (0.18 g, 0.463 mmol) in tetrahydrofuran (4.63 mL) wastreated with one drop of dimethylformamide followed by drop-wiseaddition of oxalyl chloride (0.122 mL, 1.390 mmol), stirred for twentyminutes and concentrated.

Example 45b methyl[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetate

Example 45a (0.058 g, 0.143 mmol) in tetrahydrofuran (4 mL) was treatedwith methanol (5 mL, 124 mmol), stirred for 1 hour at room temperatureand concentrated. Purification by chromatography (silica gel, 0.5-3%methanol in dichloromethane) afforded the title compound (0.048 g, 79%).¹H NMR (300 MHz, DMSO-d₆) δ 3.52 (s, 3H) 3.62 (s, 3H) 3.66 (s, 2H) 5.09(s, 2H) 6.15-6.20 (m, 1H) 7.10-7.37 (m, 10H) 11.97 (s, 1H). MS (ESI+)m/z 403.0 (M+H)⁺.

Example 462-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-ethylacetamide

Example 46 was prepared according to the procedure used for thepreparation of Example 45b, substituting ethylamine for methanol, toprovide the title compound (0.039 g, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ1.01 (t, J=7.29 Hz, 3H) 2.99-3.11 (m, 2H) 3.35 (s, 2H) 3.52 (s, 3H) 5.07(s, 2H) 6.14-6.21 (m, 1H) 7.08-7.35 (m, 10H) 7.98 (t, J=5.43 Hz, 1H)11.96 (s, 1H). MS (ESI+) m/z 416.0 (M+H)⁺.

Example 472-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N,N-dimethylacetamide

Example 47 was prepared according to the procedure used for thepreparation of Example 45b, substituting dimethylamine for methanol, toprovide the title compound (0.058 g, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ2.83 (s, 3H) 3.02 (s, 3H) 3.52 (s, 3H) 3.66 (s, 2H) 5.08 (s, 2H)6.12-6.24 (m, 1H) 7.06-7.36 (m, 10H) 11.96 (s, 1H). MS (ESI+) m/z 416.0(M+H)⁺.

Example 48N-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 48a4-(2-(3,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 48a was prepared according to the procedure used for thepreparation of Example 2b, substituting 3,4-difluorophenol for phenol,to provide the title compound.

Example 48b4-(5-amino-2-(3,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 48b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 48a forthe product of Example 2b, to provide the title compound.

Example 48cN-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 48c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 48b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ3.04 (s, 3H), 3.50 (s, 3H), 6.28-6.23 (m, 1H), 6.72-6.62 (m, 1H), 6.97(ddd, J=11.9, 6.7, 3.0 Hz, 1H), 6.97 (ddd, J=11.9, 6.7, 3.0 Hz, 1H),7.11 (d, J=8.7 Hz, 1H), 7.41-7.19 (m, 5H), 9.78 (s, 1H), 12.03 (bs, 1H).MS (ESI+) m/z 446.1 (M+H)⁺.

Example 49N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]methanesulfonamideExample 49a6-methyl-4-(5-nitro-2-(2,4,6-trifluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 49a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2,4,6-trifluorophenol forphenol, to provide the title compound.

Example 49b4-(5-amino-2-(2,4,6-trifluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 49b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 49a forthe product of Example 2b, to provide the title compound.

Example 49cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]methanesulfonamide

Example 49c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 49b for the product ofExample 3, to provide the title compound. 1H¹H NMR NMR (300 MHz,DMSO-d₆) δ 2.99 (s, 3H), 3.57 (s, 3H), 6.23 (t, J=2.3 Hz, 1H), 6.80 (d,J=8.8 Hz, 1H), 7.15 (dd, J=8.8, 2.7 Hz, 1H), 7.34-7.27 (m, 3H),7.45-7.34 (m, 2H), 9.66 (s, 1H), 12.07 (bs, 1H). MS (ESI+) m/z 464.1(M+H)⁺.

Example 504-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamideExample 50a ethyl4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate

Example 50a was prepared according to the procedure used for thepreparation of Example 9b, substituting 2,4-difluorophenol for phenol,to provide the title compound.

Example 50b4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoicacid

Example 50b was prepared according to the procedure used for thepreparation of Example 10, substituting Example 50a for Example 9b, toprovide the title compound.

Example 50c4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 50c was prepared according to the procedure used for thepreparation of Example 13a, substituting Example 50b for Example 10, toprovide the title compound.

Example 50d4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 50d was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 50c for Example 13a,and aqueous ammonium hydroxide for ethylamine, respectively, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.57 (s, 3H), 6.24-6.25(m, 1H), 6.83 (d, J=8.24 Hz, 1H), 7.07-7.13 (m, 1H), 7.27-7.34 (m, 4H),7.42-7.48 (m, 1H), 7.85 (dd, J=8.54, 2.44, 1H), 7.96 (s, 1H), 8.00 (d,J=2.44 Hz, 1H), 12.04 (s, 1H). MS (ESI+) m/z 396.3 (M+H)⁺.

Example 514-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydrofuran-3-yl)benzamide

Example 51 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 50c for Example 13a,and tetrahydrofuran-3-amine for ethylamine, respectively, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.87-1.94 (m, 1H), 2.10-2.19(m, 1H), 3.57 (s, 3H), 3.67-3.73 (m, 2H), 3.81-3.87 (m, 2H), 4.42-4.49(m, 1H), 6.22-6.23 (m, 1H), 6.85 (d, J=8.54 Hz, 1H), 7.07-7.13 (m, 1H),7.25-7.34 (m, 3H), 7.42-7.47 (m, 1H), 7.85 (dd, J=8.85, 2.14, 1H), 7.96(s, 1H), 8.00 (d, J=2.14 Hz, 1H), 8.50 (d, J=6.41 Hz, 1H), 12.03 (s,1H). MS (ESI+) m/z 466.3 (M+H)⁺.

Example 524-{2-(2,4-difluorophenoxy)-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 52 was prepared according to the procedure used for thepreparation of Example 13b, substituting 1,1-dioxo-1-thiomorpholine forethylamine and Example 50c for Example 13a, respectively, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.25-3.28 (m, 4H), 3.56 (s,3H), 3.78 (m, 4H), 4.45-4.61 (m, 1H), 3.81-3.87 (m, 2H), 6.26-6.27 (m,1H), 6.86 (d, J=8.24 Hz, 1H), 7.07-7.12 (m, 1H), 7.27-7.33 (m, 3H),7.42-7.48 (m, 2H), 7.63 (d, J=2.14, 1H), 12.04 (s, 1H). MS (ESI+) m/z514.2 (M+H)⁺.

Example 534-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(1-methyl-2-oxopyrrolidin-3-yl)benzamide

Example 53 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 50c for Example 13a,and 3-amino-1-methylpyrrolidin-2-one for ethylamine, respectively, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.87-1.97 (m,1H), 2.29-2.38 (m, 1H), 2.76 (s, 3H), 3.30-3.34 (m, 2H), 3.57 (s, 3H),4.45-4.61 (m, 1H), 3.81-3.87 (m, 2H), 4.42-4.49 (m, 1H), 6.23-6.24 (m,1H), 6.87 (d, J=8.54 Hz, 1H), 7.08-7.13 (m, 1H), 7.25-7.34 (m, 3H),7.43-7.48 (m, 1H), 7.85 (dd, J=8.54, 2.44 Hz, 1H), 7.96 (s, 1H), 7.99(d, J=2.14 Hz, 1H), 8.73 (d, J=8.85 Hz, 1H), 12.03 (s, 1H). MS (ESI+)m/z 493.2 (M+H)⁺.

Example 54 tert-butyl{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]pyrrolidin-3-yl}carbamate

Example 54 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 50c for Example 13a,and tert-butyl pyrrolidin-3-ylcarbamate for ethylamine, respectively, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.33-1.40 (m,9H), 1.74-1.83 (m, 1H), 2.01-2.0.3 (m, 1H), 3.27-3.31 (m, 1H), 3.56 (s,3H), 3.62-3.56 (m, 1H), 3.93-4.07 (m, 1H), 6.24 (d, J=2.29 Hz, 1H), 6.83(d, J=8.54 Hz, 1H), 7.0-7.13 (m, 1H), 7.20-7.33 (m, 3H), 7.41-7.52 (m,2H), 7.60 (d, J=16.2 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 565.2 (M+H)⁺.

Example 554-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylcarbonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 55 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 50c for Example 13a,and pyrrolidine for ethylamine, respectively, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.82-1.86 (m, 4H), 3.45-3.48 (m,4H), 3.56 (s, 3H), 6.24-6.26 (m, 1H), 6.82 (d, J=8.24 Hz, 1H), 7.06-7.12(m, 1H), 7.26-7.33 (m, 3H), 7.41-7.46 (m, 1H), 7.52 (dd, J=8.54, 2.14Hz, 1H), 7.61 (d, J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 450.3(M+H)⁺.

Example 564-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylcarbonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 56 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 50c for Example 13a,and morpholine for ethylamine, respectively, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.56 (s, 3H), 3.60-3.68 (m, 8H),6.24-6.25 (m, 1H), 6.84 (d, J=8.54 Hz, 1H), 7.06-7.12 (m, 1H), 7.26-7.33(m, 3H), 7.40 dd, J=8.54, 2.14 Hz, 1H), 7.44-7.46 (m, 1H), 7.50 (dd,J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 466.3 (M+H)⁺.

Example 57N-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 57a4-(2-(cyclohexyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 57a was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclohexanol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 57b4-(5-amino-2-(cyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 57b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 57a forthe product of Example 2b, to provide the title compound.

Example 57cN-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 57c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 57b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.47-1.10 (m, 6H), 1.61-1.47 (m, 2H), 1.84-1.69 (m, 2H), 2.94 (s, 3H),3.55 (s, 3H), 4.31-4.22 (m, 1H), 6.21 (t, J=2.3 Hz, 1H), 7.18-7.06 (m,2H), 7.31-7.25 (m, 3H), 9.39 (s, 1H), 11.98 (bs, 1H). MS (ESI+) m/z416.2 (M+H)⁺.

Example 58N-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 58a4-(2-(cyclopentyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 58a was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopentanol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 58b4-(5-amino-2-(cyclopentyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 58b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 58a forthe product of Example 2b, to provide the title compound.

Example 58cN-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 58c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 58b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.70-1.43 (m, 6H), 1.88-1.70 (m, 2H), 2.94 (s, 3H), 3.55 (s, 3H),4.78-4.70 (m, 1H), 6.16 (t, J=2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.16(dd, J=8.7, 2.7 Hz, 1H), 7.22 (s, 1H), 7.30-7.23 (m, 2H), 9.39 (s, 1H),11.97 (bs, 1H). MS (ESI+) m/z 402.1 (M+H)⁺.

Example 59N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamideExample 59a4-(2-(4,4-difluorocyclohexyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 59a was prepared according to the procedure used for thepreparation of Example 29a, substituting 4,4-difluorocyclohexanol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 59b4-(5-amino-2-(4,4-difluorocyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 59b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 59a forthe product of Example 2b, to provide the title compound.

Example 59cN-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide

Example 59c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 59b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.95-1.61 (m, 8H), 2.95 (s, 3H), 3.55 (s, 3H), 4.55-4.46 (m, 1H),6.22-6.17 (m, 1H), 7.20-7.15 (m, 2H), 7.31-7.25 (m, 3H), 9.47 (s, 1H),12.01 (bs, 1H). MS (ESI+) m/z 452.2 (M+H)⁺.

Example 60N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]methanesulfonamideExample 60a6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 60a was prepared according to the procedure used for thepreparation of Example 29a, substituting tetrahydro-2H-pyran-3-ol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 60b4-(5-amino-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 60b was prepared according to the procedure used for thepreparation of Example 29b, substituting the product of Example 60a forthe product of Example 29a, to provide the title compound.

Example 60cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]methanesulfonamide

Example 60c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 60b for the product ofExample 3, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ1.39-1.45 (m, 1H), 1.55-1.70 (m, 2H), 1.89-1.96 (m, 1H), 2.95 (s, 3H),3.41-3.57 (m, 7H), 3.65-3.69 (m, 1H), 6.24-6.26 (m, 1H), 6.84 (d, J=8.54Hz, 1H), 7.14 (m, 2H), 7.29-7.31 (m, 2H), 7.38 (s, 1H), 9.45 (s, 1H),12.03 (s, 1H). MS (ESI+) m/z 418.2 (M+H)⁺.

Example 616-methyl-4-[2-(morpholin-4-ylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 61 was prepared according to the procedure used for thepreparation of Example 1f, substitutingmorpholino(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanonefor 2-phenoxyphenylboronic acid, followed by purification by preparativeHPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ 2.80-2.83 (m, 2H), 2.91-2.99(m, 2H), 3.20-3.25 (m, 2H), 3.54-3.57 (m, 5H), 6.17-6.18 (m, 1H), 7.06(s, 1H), 7.32 (t, J=2.9 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.42-7.53 (m,3H), 1H), 12.15 (s, 1H). MS (ESI+) m/z 338.1 (M+H)⁺.

Example 62N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide

Example 62 was prepared according to the procedure used in method A ofExample 4, substituting Example 33b for Example 3 and substitutingethanesulfonyl chloride for methanesulfonyl chloride respectively toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (t, J=7.3Hz, 3H), 3.09 (q, J=7.3 Hz, 2H), 3.56 (s, 3H), 6.22 (t, J=2.3 Hz, 1H),6.79 (d, J=8.8 Hz, 1H), 7.15 (dd, J=8.8, 2.7 Hz, 1H), 7.44-7.27 (m, 5H),9.72 (s, 1H), 12.06 (bs, 1H). MS (ESI+) m/z 478.1 (M+H)⁺.

Example 63N-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 63a4-(2-(benzyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 63a was prepared according to the procedure used for thepreparation of Example 29a, substituting phenylmethanol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 63b4-(5-amino-2-(benzyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 63b was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 63a forthe product of Example 2b, to provide the title compound.

Example 63cN-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 63c was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 63b for the product ofExample 3, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ2.94 (s, 3H), 3.51 (s, 3H), 5.07 (s, 2H), 6.24-6.18 (m, 1H), 7.22-7.16(m, 2H), 7.37-7.24 (m, 8H), 9.45 (s, 1H), 12.00 (bs, 1H). MS (ESI+) m/z424.2 (M+H)⁺.

Example 64N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide

Example 64 was prepared according to the procedure used for thepreparation of Example 27c, substituting 2-fluoroethanesulfonyl chloridefor methanesulfonyl chloride, and bypassing the sodium hydroxidehydrolysis step, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 3.52 (s, 3H), 3.63 (t, J=6.0 Hz, 2H), 4.12 (q, J=6.0 Hz, 2H),6.25-6.19 (m, 1H), 7.08-6.62 (m, 5H), 7.27-7.20 (m, 3H), 11.99-11.92 (m,1H). MS (ESI+) m/z 478.2 (M+H)⁺.

Example 65N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N′-methylsulfuricdiamide

Example 65 was prepared according to the procedure used for thepreparation of Example 27c, substituting methylsulfamoyl chloride formethanesulfonyl chloride, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 2.50 (m, 3H solvent obscured), 3.52 (s, 3H), 6.28-6.22(m, 1H), 7.08-6.86 (m, 3H), 7.15 (dd, J=8.8, 2.7 Hz, 1H), 7.39-7.21 (m,5H), 9.65 (s, 1H), 12.02 (bs, 1H), MS (ESI+) m/z 461.1 (M+H)⁺.

Example 66N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide

Example 66 was prepared according to the procedure used in method A ofExample 4, substituting the product of Example 31b for the product ofExample 3, and ethanesulfonyl chloride for methanesulfonyl chloride,respectively, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ1.22 (t, J=7.3 Hz, 3H), 1.93-1.80 (m, 1H), 2.20-2.04 (m, 1H), 3.02 (q,J=7.3 Hz, 2H), 3.55 (s, 3H), 3.65 (m, 3H), 3.82 (dd, J=10.0, 4.5 Hz,1H), 5.00-4.91 (m, 1H), 6.16 (t, J=2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H),7.16 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (s, 1H), 7.31-7.25 (m, 3H), 9.53 (s,1H), 12.01 (bs, 1H), MS (ESI+) m/z 418.1 (M+H)⁺.

Example 67 methyl6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylateExample 67a ethyl4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Diisopropylamine (0.111 g, 1.102 mmol) in tetrahydrofuran (3 mL) wastreated with BuLi (2.5 M, 0.44 mL, 1.102 mmol) at −78° C. The solutionwas stirred for 20 minutes at −78° C., and warmed up to room temperaturefor 5 minutes, and cooled down to −78° C. again. To this solution wasadded N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (0.128 g, 1.102 mmol).Then Example 1e (0.30 g, 0.787 mmol) in tetrahydrofuran (3 mL) was addedto the reaction mixture via cannula under nitrogen. The reaction mixturewas stirred at −78° C. for 1 hour, warmed to 0° C. briefly, and cooleddown to −78° C. To this suspension was added ethyl carbonochloridate(0.205 g, 1.889 mmol) via a syringe. The reaction mixture was allowed towarm to room temperature gradually overnight. The mixture was thenpartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate three times. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel eluting with 30-50% ethyl acetate in hexanes to afford 0.074 g ofthe title compound.

Example 67b methyl6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 67b was prepared according to the procedure used for thepreparation of Example 1f, substituting Example 67a for Example 1e, andbypassing the use of potassium carbonate, followed by purification bypreparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.50 (s, 3H),3.80 (s, 3H), 6.80-6.82 (m, 3H), 7.00 (t, J=7.32 Hz, 1H), 7.06 (d,J=7.02 Hz, 1H), 7.23-7.32 (m, 4H), 7.40-7.42 (m, 1H), 7.52 (dd, J=7.48,1.68 Hz, 1H), 12.85 (s, 1H). MS (ESI+) m/z 375 (M+H)⁺.

Example 68 methyl1,6-dimethyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

The title compound was obtained as a by-product from the preparation ofExample 67b. ¹H NMR (500 MHz, DMSO-d₆) δ 3.48 (s, 3H), 3.81 (s, 3H),4.38 (s, 3H), 6.81-6.84 (m, 3H), 6.98-7.07 (m, 2H), 7.25-7.31 (m, 3H),7.34 (s, 1H), 7.41-7.47 (m, 1H), 7.48 (dd, J=7.48, 1.68 Hz, 1H). MS(ESI+) m/z 389 (M+H)⁺.

Example 69 ethyl4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylateExample 69a ethyl1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 69a was prepared according to the procedure used for thepreparation of Example 2a (Method B), substituting Example 67a forExample 1e, to provide the title compound.

Example 69b ethyl6-methyl-4-(5-nitro-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 69b was prepared according to the procedure used for thepreparation of Example 2b, substituting Example 69a for Example 2a, toprovide the title compound.

Example 69c ethyl4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 69c was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 69b for Example 29a,and purified by preparative HPLC (C18, 10-100% acetonitrile in 0.1%TFA/water) to provide the TFA salt of the title compound. ¹H NMR (500MHz, DMSO-d₆) δ 1.30 (t, J=7.02 Hz, 3H), 3.49 (s, 3H), 4.27 (q, J=7.12Hz, 2H), 6.77 (d, J=7.93 Hz, 2H), 6.86 (d, J=2.14 Hz, 1H), 6.93-7.03 (m,3H), 7.11 (s, 1H), 7.20-7.24 (m, 2H), 7.31 (s, 1H), 12.86 (s, 1H). MS(ESI+) m/z 404.1 (M+H)⁺.

Example 706-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid Example 70a (Z)-ethyl3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-hydroxyacrylate

To a solution of ethanol (15 mL) and ether (150 mL) were added5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60 mmol), diethyloxalate (13.15 g, 90 mmol), and potassium ethoxide (6.06 g, 72 mmol).The reaction mixture was heated at 45° C. for 24 hours. During thereaction, the flask was shaken by hand several times. After cooling, thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate three times.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 10-20% ethyl acetate inhexanes to 9.5 g of the title compound (yield 46%).

Example 70b ethyl4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture Example 70a (9.5 g, 27.4 mmol) and iron (7.64 g, 137 mmol) inethanol (60 mL) and acetic acid (60 mL) was heated at 100° C. for 1hour. The solution turned from red to gray. The solid was filtered off,and then washed with additional ethyl acetate. The solvents were removedunder reduced pressure to 20% of original volume, and it was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate several times. The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel eluting with20-40% ethyl acetate in hexanes to afford 6.05 g of the title compound.

Example 70c ethyl1-benzyl-4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL) was treatedwith 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g of a 60% in oildispersion). The solution was stirred at room temperature for 10minutes. To this solution was added benzyl bromide (0.59 g, 3.45 mmol).The reaction mixture was stirred for another 2 hours. It was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate twice. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash chromatography on silica gel eluting with 20-40%ethyl acetate in hexanes to afford 1.07 g of the title compound.

Example 70d ethyl1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70d was prepared according to the procedure used for thepreparation of Example 1d, substituting Example 70c for Example 1c, toprovide the title compound.

Example 70e ethyl1-benzyl-4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylat

Example 70e was prepared according to the procedure used for thepreparation of Example 1e, substituting Example 70d for Example 1d, toprovide the title compound.

Example 70f ethyl1-benzyl-4-(2-fluoro-5-nitrophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70f was prepared according to the procedure used for thepreparation of Example 2a (Method B), substituting Example 70e forExample 1e, to provide the title compound.

Example 70g ethyl1-benzyl-6-methyl-4-(5-nitro-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70g was prepared according to the procedure used for thepreparation of Example 2b, substituting Example 70f for Example 2a, toprovide the title compound.

Example 70h ethyl4-(5-amino-2-phenoxyphenyl)-1-benzyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70h was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 70g for Example 29a, toprovide the title compound.

Example 70i ethyl1-benzyl-6-methyl-4-(5-(N-(methylsulfonyl)methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70i was prepared according to the procedure used in method A ofExample 4, substituting Example 70h for Example 3, except the use of 1 MNaOH, to provide the title compound.

Example 70j ethyl6-methyl-4-(5-(N-(methylsulfonyl)methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 70i (0.53 g, 0.816 mmol), anisole (0.176 g, 1.631mmol), and concentrated H₂SO₄ (0.5 mL) in TFA (10 mL) was heated at 90°C. for 4 hours. Excess TFA was removed under reduced pressure, and theresidue was partitioned between water and ethyl acetate. The organiclayer was separated, and the aqueous layer was extracted with additionalethyl acetate several times. The combined organic layers were washedwith saturated aqueous sodium bicarbonate, followed by brine, dried overMgSO₄, filtered, and concentrated to afford 0.48 g of the titlecompound. The crude material was used directly for the next reaction.

Example 70k6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

Example 70j (0.4 g, 0.858 mmol) in dioxane (5 mL) was treated with 2.0 NNaOH (1.72 mL, 3.43 mmol). The reaction mixture was heated at 65° C. for2 hours. The reaction mixture was cooled to room temperature and pouredinto water (100 mL). After addition of concentrated HCl (1 mL), themixture was extracted with ethyl acetate three times (3×30 mL). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to afford 0.36 g (93%) of the title compound.A small amount of sample was purified by preparative HPLC (C18, 10-70%acetonitrile in 0.1% TFA/water) to provide the TFA salt of the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.03 (s, 3H), 3.49 (s, 3H), 6.81(d, J=7.63 Hz, 2H), 6.84 (d, J=2.14 Hz, 1H), 6.96-7.00 (m, 1H), 7.08 (d,J=8.85 Hz, 1H), 7.22-7.27 (m, 3H), 7.34 (s, 1H), 7.37 (d, J=2.75 Hz,1H), 9.77 (s, 1H), 12.62 (d, J=1.53 Hz, 1H), 13.00 (s, br, 1H). MS(ESI+) m/z 454.1 (M+H)⁺.

Example 71 ethyl6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 70k (0.2 g, 0.441 mmol) in ethanol (10 mL) was treated withconcentrated H₂SO₄ (0.5 mL). The reaction mixture was heated underreflux overnight. The solvent was removed, and the remaining waspartitioned between water and ethyl acetate. The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate several times. The combined organic layers were washed with sat.NaHCO₃, brine, dried over MgSO₄, filtered, and concentrated to afford0.19 g of the title compound. A small amount of crude product waspurified by preparative HPLC to provide clean product for biologicaltesting. ¹H NMR (500 MHz, DMSO-d₆) δ 1.30 (t, J=7.17 Hz, 3H), 3.04 (s,3H), 3.50 (s, 3H), 4.26 (q, J=7.22 Hz, 2H), 6.80 (d, J=7.63 Hz, 2H),6.86 (d, J=2.14 Hz, 1H), 6.96-7.00 (m, 1H), 7.09 (d, J=8.85 Hz, 1H),7.21-7.28 (m, 3H), 7.35 (s, 1H), 7.36 (d, J=2.75 Hz, 1H), 9.78 (s, 1H),12.86 (s, 1H). (ESI+) m/z 482.1 (M+H)⁺.

Example 72N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 72a6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbonylchloride

Example 72a was prepared according to the procedure used for thepreparation of Example 13a, substituting Example 70k for Example 10, toprovide the title compound.

Example 72bN-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 72b was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 72a for Example 13a, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.12 (t, J=7.17Hz, 3H), 3.03 (s, 3H), 3.23-3.30 (M, 2H), 3.49 (s, 3H), 6.81 (d, J=7.63Hz, 2H), 6.86 (d, J=2.44 Hz, 1H), 6.96-7.00 (m, 1H), 7.07 (d, J=8.54 Hz,1H), 7.22-7.28 (m, 3H), 7.30 (s, 1H), 7.34 (d, J=2.75 Hz, 1H), 8.34 (t,J=5.34 Hz, 1H), 9.79 (s, 1H), 12.22 (s, 1H). (ESI+) m/z 481.1 (M+H)⁺.

Example 736-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 73 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 72a for Example 13a,and aqueous ammonium hydroxide for ethyl amine, respectively, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.03 (s, 3H), 3.50 (s,3H), 6.82 (d, J=7.63 Hz, 2H), 6.88 (d, J=2.44 Hz, 1H), 6.97-7.01 (m,1H), 7.06 (d, J=8.54 Hz, 1H), 7.22-7.28 (m, 3H), 7.31 (s, 1H), 7.35 (d,J=2.75 Hz, 1H), 7.46 (s, 1H), 7.81 (s, 1H), 9.78 (s, 1H), 12.22 (s, 1H).MS (ESI+) m/z 453.1 (M+H)⁺.

Example 74 ethyl4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylateExample 74a 4-amino-6-chloro-2-methylpyridazin-3 (2H)-one

A mixture of 4,6-dichloro-2-methylpyridazin-3(2H)-one (5.0 g, 27.9 mmol)and ammonium hydroxide (55 mL, 1412 mmol) was heated at 150° C. for 2hours and then cooled to room temperature. The solvent was removed, andthe residue was dissolved in ethyl acetate and washed with water. Theaqueous layer was extracted with additional ethyl acetate three times.The combined organic layers were washed with brine, dried andconcentrated. The residue was purified by flash chromatography (silicagel, eluted with 40% ethyl acetate in hexanes to afford 3.85 g (87%) ofthe title compound.

Example 74b 4-amino-6-chloro-5-iodo-2-methylpyridazin-3(2H)-one

A mixture of Example 74a (2.12 g, 13.3 mmol) and N-iodosuccinimide (5.38g, 23.9 mmol) in acetonitrile (30 mL) was heated under reflux for 6hours. The reaction mixture was cooled to room temperature andpartitioned between ethyl acetate and water. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 20-40% ethyl acetate inhexanes to afford 3.27 g (86%) of the title compound.

Example 74c4-chloro-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylicacid

A mixture of Example 74b (0.59 g, 2.1 mmol), pyruvic acid (0.546 g, 6.2mmol), 1,4-diazabicyclo[2.2.2]octane (0.695 g, 6.2 mmol), andpalladium(II)acetate (0.046 g, 10 mol %) in dimethylformamide (8 mL) wasdegassed and back-filled with nitrogen three times. The reaction mixturewas then heated at 105° C. overnight. The reaction mixture was cooled toroom temperature and partitioned between ethyl acetate and water. Theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue wastriturated in 30% ethyl acetate in hexanes to afford 0.25 g (53%) of thetitle compound.

Example 74d ethyl4-chloro-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylate

Example 74c (0.45 g, 2.0 mmol) in ethanol (15 mL) was treatedconcentrated sulfuric acid (1 mL). The reaction mixture was heated underreflux for 16 hours. The reaction mixture was cooled to room temperatureand partitioned between ethyl acetate and water. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated to afford 0.45 g (89%) of the title compound.

Example 74e ethyl4-chloro-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylate

A solution of Example 74d (0.41 g, 1.6 mmol) in dimethylformamide (15mL) was treated with 60% sodium hydride (0.096 g, 2.4 mmol) at roomtemperature. The reaction mixture was stirred for 30 min, and then wastreated with (2-(chloromethoxy)ethyl)trimethylsilane (0.40 g, 2.4 mmol).The reaction mixture was then stirred for 2 hours. It was partitionedbetween ethyl acetate and water. The aqueous layer was extracted withadditional ethyl acetate twice. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 20% ethyl acetate to afford 0.50 g (81%) of the titlecompound.

Example 74f ethyl4-(2-fluoro-5-nitrophenyl)-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylate

Example 74f was prepared according to the procedure used for thepreparation of Example 2a (Method B), substituting Example 74e forExample 1e, to provide the title compound

Example 74g ethyl6-methyl-4-(5-nitro-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylate

A mixture of Example 74f (0.26 g, 0.53 mmol), phenol (0.060 g, 0.64mmol) and cesium carbonate (0.21 g, 0.63 mmol) in dimethylsulfoxide (5mL) was heated at 110° C. for 6 hours. After cooling to roomtemperature, the reaction mixture was partitioned between water andethyl acetate. The aqueous layer was extracted with additional ethylacetate three times. The combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was then treated with 15 mL of ethanol and 1 mL of concentratedH₂SO₄. The mixture was heated under reflux overnight. The reactionmixture was cooled to room temperature and partitioned between ethylacetate and water. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 40-80% ethylacetate to afford 0.14 g (61%) of the title compound.

Example 74h ethyl4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate

Example 74h was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 74g for Example 29a,and ethanol for ethyl acetate, respectively, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.29 (t, J=7.02 Hz, 3H), 3.61 (s,3H), 4.28 (q, J=7.22 Hz, 2H), 5.22 (s, 2H), 6.65 (d, J=7.33 Hz, 2H),6.74 (dd, J=8.85, 2.75 Hz, 1H), 6.79 (t, J=2.75 Hz, 1H), 6.87 (d, J=7.32Hz, 1H), 6.91-6.93 (m, 2H), 7.13-7.17 (m, 2H), 13.37 (br s, 1H). MS(ESI+) m/z 405.1 (M+H)⁺.

Example 75 ethyl4-[5-(ethylamino)-2-phenoxyphenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate

Example 75 was obtained as a by-product from the preparation of Example74h ¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (t, J=7.17 Hz, 3H), 1.30 (t, J=7.02Hz, 3H), 3.03-3.08 (m, 2H), 3.62 (s, 3H), 4.29 (q, J=7.02 Hz, 2H), 5.71(t, J=5.19 Hz, 1H), 6.65 (d, J=7.63 Hz, 2H), 6.72-6.74 (m, 2H), 6.87 (t,J=7.32 Hz, 1H), 6.91 (s, 1H), 6.99 (d, J=9.16 Hz, 1H), 7.13-7.17 (m,2H), 13.47 (br s, 1H). MS (ESI+) m/z 433.1 (M+H)⁺.

Example 76 ethyl4-{5-[ethyl(methylsulfonyl)amino]-2-phenoxyphenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate

Example 76 was prepared according to the procedure used in method A ofExample 4, substituting Example 75 for Example 3, except the use ofNaOH, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.07(t, J=7.02 Hz, 3H), 1.30 (t, J=7.17 Hz, 3H), 3.02 (s, 3H), 3.67-3.72 (m,5H), 4.23 (q, J=7.22 Hz, 2H), 6.93 (d, J=7.93 Hz, 2H), 6.99 (d, J=2.14Hz, 1H), 7.07-7.12 (m, 2H), 7.30-7.34 (m, 2H), 7.52-7.55 (m, 1H), 7.85(d, J=2.75 Hz, 1H). MS (ESI+) m/z 511.1 (M+H)⁺.

Example 776-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylicacid

Example 77 was prepared according to the procedure used in method A ofExample 4, substituting Example 74h for Example 3, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.04 (s, 3H), 3.66 (s, 3H),6.39-6.40 (m, 1H), 6.81-6.83 (m, 2H), 6.93 (d, J=1.53 Hz, 1H), 6.98-7.01(m, 1H), 7.14 (d, J=8.85 Hz, 1H), 7.23-7.27 (m, 2H), 7.37-7.42 (m, 1H),7.43 (d, J=2.75 Hz, 1H), 9.82 (s, 1H), 13.35 (s, 1H). MS (ESI+) m/z455.1 (M+H)⁺.

Example 786-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamideExample 78a6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carbonylchloride

Example 78a was prepared according to the procedure used for thepreparation of Example 13a, substituting Example 77 for Example 10, toprovide the title compound.

Example 78b6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide

Example 78b was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 78a for Example 13a,and aqueous ammonium hydroxide for ethylamine, respectively, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.03 (s, 3H), 3.67 (s,3H), 6.85 (d, J=7.63 Hz, 2H), 6.99-7.04 (m, 2H), 7.10 (d, J=8.54 Hz,1H), 7.23-7.28 (m, 2H), 7.37-7.40 (m, 2H), 7.57 (s, 1H), 7.91 (s, 1H),9.82 (s, 1H), 12.95 (s, 1H). MS (ESI+) m/z 454.1 (M+H)⁺.

Example 796-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide

Example 79 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 78a for Example 13a,and 2-(4-methylpiperazin-1-yl)ethanamine for ethylamine, respectively,to provide the TFA salt of the title compound. ¹H NMR (500 MHz, DMSO-d₆)δ 2.67-2.80 (m, 6H), 3.04 (s, 3H), 3.49 (br, 8H), 3.67 (s, 3H), 6.82 (d,J=7.63 Hz, 2H), 6.99-7.03 (m, 2H), 7.13 (d, J=8.85 Hz, 1H), 7.24-7.28(m, 2H), 7.37-7.40 (m, 2H), 8.50-8.52 (m, 1H), 9.85 (s, 1H), 13.03 (s,1H). MS (ESI+) m/z 580.2 (M+H)⁺.

Example 80N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-phenoxyphenyl]methanesulfonamideExample 80a(E)-4-amino-6-chloro-5-(2-ethoxyvinyl)-2-methylpyridazin-3(2H)-one

Example 80a was prepared according to the procedure used for thepreparation of Example 2a (Method B), substituting Example 74b forExample 1e, and(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for2-fluoro-5-nitrophenylboronic acid, respectively, to provide the titlecompound.

Example 80b 4-chloro-6-methyl-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one

Example 80a (0.1 g, 0.435 mmol) in acetic acid (5 mL) was heated at 90°C. overnight. The solvent was evaporated under reduced pressure toafford 0.071 g of the title compound.

Example 80c4-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one

Example 80c was prepared according to the procedure used for thepreparation of Example 74e, substituting Example 80b for Example 74c, toprovide the title compound.

Example 80d4-(2-fluoro-5-nitrophenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one

Example 80d was prepared according to the procedure used for thepreparation of Example 2a (Method B), substituting Example 80c forExample 1e, to provide the title compound.

Example 80e6-methyl-4-(5-nitro-2-phenoxyphenyl)-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one

Example 80e was prepared according to the procedure used for thepreparation of Example 2b, substituting Example 80d for Example 2a, toprovide the title compound.

Example 80f4-(5-amino-2-phenoxyphenyl)-6-methyl-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one

Example 80f was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 80e for Example 29a, toprovide the title compound.

Example 80gN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-phenoxyphenyl]methanesulfonamide

Example 80g was prepared according to the procedure used in method A ofExample 4, substituting Example 80f for Example 3, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.03 (s, 3H), 3.67 (s, 3H),6.39-6.40 (m, 1H), 6.87 (d, J=7.63 Hz, 2H), 7.01 (t, J=7.48 Hz, 1H),7.08 (d, J=8.54 Hz, 1H), 7.24-7.28 (m, 2H), 7.35 (dd, J=8.85, 2.75 Hz,1H), 7.42-7.43 (m, 2H), 9.80 (s, 1H), 12.67 (s, 1H). MS (ESI+) m/z 411.1(M+H)⁺.

Example 81N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide

Example 81 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 78a for Example 13a, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.12 (t, J=7.17Hz, 3H), 3.03 (s, 3H), 3.27-3.30 m, 2H), 3.66 (s, 3H), 6.82-6.84 (m,2H), 6.98-7.02 (m, 2H), 6.97-7.01 (m, 1H), 7.12 (d, J=9.16 Hz, 1H),7.23-7.28 (m, 2H), 7.37-7.40 (m, 2H), 8.44 (t, J=5.34 Hz, 1H), 9.83 (s,1H), 12.97 (s, 1H). MS (ESI+) m/z 482.1 (M+H)⁺.

Example 826-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

Example 82 was prepared according to the procedure used for thepreparation of Example 1f, substituting Example 80b for Example 1e,except for the use of potassium carbonate, followed by purification bypreparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.70 (s, 3H),6.36-6.37 (m, 1H), 6.91-6.93 (m, 2H), 7.02-7.07 (m, 2H), 7.27-7.31 (m,3H), 7.41 (t, J=2.75 Hz, 1H), 7.47-7.52 (m, 1H), 7.56 (dd, J=7.63, 1.83Hz, 1H), 12.65 (s, 1H). MS (ESI+) m/z 318.1 (M+H)⁺.

Example 83N-ethyl-N,6-dimethyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide

Example 83 was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 78a for Example 13a,and N-methylethanamine for ethylamine, respectively, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.07 (br, 3H), 2.94 (s, 3H),3.03 (s, 3H), 3.45 (br, 2H), 3.68 (s, 3H), 6.88 (d, J=7.93 Hz, 2H), 7.01(t, J=7.32 Hz, 1H), 7.12 (d, J=8.85 Hz, 1H), 7.24-7.28 (m, 2H), 7.36(dd, J=8.85, 2.75 Hz, 1H), 7.43 (d, J=2.75 Hz, 1H), 9.81 (s, 1H), 13.01(s, 1H). MS (ESI+) m/z 496.1 (M+H)⁺.

Example 844-{4-[(ethylsulfonyl)amino]-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy}benzamide

To a mixture of Example 33b (50 mg, 0.14 mmol) and triethylamine (0.043g, 0.42 mmol) in dichloromethane (4 mL) was added dropwiseethanesulfonyl chloride (0.072 g, 0.56 mmol), and the reaction mixturestirred at ambient temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, dioxane (4 mL) and sodium hydroxide(10% w/v, 3 mL, 0.14 mmol) were added, and the reaction mixture washeated at 70° C. for 1 hour. The mixture was cooled to ambienttemperature and then neutralized with saturated aqueous ammoniumchloride (50 mL) to a pH of 7. The organic layer was separated and theaqueous phase was extracted with ethyl acetate (3×25 mL). The combinedorganic layers were washed with saturated aqueous sodium chloride, dried(anhydrous magnesium sulfate), filtered, and concentrated. The residuewas purified by preparative HPLC (C18, 10-100% acetonitrile/water, 0.1%TFA) to afford the title compound (22 mg, 35%). ¹H NMR (300 MHz,DMSO-d₆) □ ppm 12.01 (s, 1H) 9.86 (s, 1H) 7.77 (s, 1H) 7.74 (d, J=8.82Hz, 2H) 7.42 (d, J=2.37 Hz, 1H) 7.22-7.30 (m, 3H) 7.18 (s, 1H) 7.11-7.16(m, 1H) 6.83 (d, J=8.82 Hz, 2H) 6.23-6.28 (m, 1H) 3.47 (s, 3H) 3.15 (q,J=7.35 Hz, 2H) 1.21-1.29 (m, 3H). MS (ESI+) m/z 467.2 (M+H)⁺.

Example 856-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 85a 4-(methylsulfonyl)-2-nitro-1-phenoxybenzene

Example 85a was prepared according to the procedure used for thepreparation of Example 2b, substituting1-fluoro-4-(methylsulfonyl)-2-nitrobenzene for Example 2a, to providethe title compound.

Example 85b 5-(methylsulfonyl)-2-phenoxyaniline

Example 85b was prepared according to the procedure used for thepreparation of Example 29b, substituting 85a for Example 29a, to providethe title compound.

Example 85c 2-iodo-4-(methylsulfonyl)-1-phenoxybenzene

Example 85b (0.27 g, 1.025 mmol) in dioxane (1 mL) was treated withconcentrated HCl (6 mL) at 0° C. The reaction mixture was stirred at 0°C. for 10 minutes. To this solution was added sodium nitrite (0.085 g,1.23 mmol) in water (1 mL). The reaction was stirred at 0° C. foranother 1 hour. To this solution was added potassium iodide (0.34 g,1.051 mmol) in water (2 mL). The reaction was stirred for 1 hour at roomtemperature. The reaction mixture was partitioned between water andethyl acetate. The organic layer was extracted with additional ethylacetate twice. The combined organic layer were washed with brine, driedover MgSO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel eluting with 10-30% ethyl acetate inhexanes to afford 0.28 g of the title product.

Example 85d6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 85d was prepared according to the procedure used for thepreparation of Example 1f, substituting 85c for Example 1e, and Example6a for 2-phenoxyphenylboronic acid, followed by purification bypreparative HPLC (C18, 10-100% acetonitril/0.1% TFA in water), toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.26 (s, 3H),3.57 (s, 3H), 6.29-6.30 (m, 1H), 7.03 (d, J=8.54 Hz, 1H), 7.11 (d,J=7.63 Hz, 2H), 7.20 (t, J=7.32 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H),7.40-7.44 (m, 3H), 7.88 (dd, J=8.54, 2.44 Hz, 1H), 8.00 (d, J=2.44 Hz,1H), 12.07 (s, 1H). MS (ESI+) m/z 395.2 (M+H)⁺.

Example 865-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamideExample 86a 5-bromo-6-chloropyridine-3-sulfonamide

5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL)was cooled to 0° C. To this solution was added 7N NH₃ in methanol (80mL). The reaction mixture was stirred over night at room temperature.The solvent was removed at low temperature, and the residue waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate three times. The combined organic layerswere washed with brine, dried (MgSO₄), filtered, and concentrated. Thesolid was purified by flash column chromatography on silica gel toafford 4.2 g of the clean product.

Example 86b 5-bromo-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide

Example 86b was prepared according to the procedure used for thepreparation of Example 29a, substituting 86a for Example 2a, andtetrahydrofuran-3-ol for tetrahydro-2H-pyran-4-ol, to provide the titlecompound.

Example 86c5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide

Example 86c was prepared according to the procedure used for thepreparation of Example 1f, substituting 86b for Example 1e, and Example6a for 2-phenoxyphenylboronic acid, followed by purification bypreparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 1.91-1.97 (m,1H), 2.18-2.25 (m, 1H), 3.59 (s, 3H), 3.66-3.76 (m, 3H), 3.92-3.95 (m,1H), 5.63-5.66 (m, 1H), 6.19-6.21 (m, 1H), 7.34 (t, J=2.75 Hz, 1H), 7.41(s, 1H), 7.47 (s, 2H), 8.14 (d, J=2.44 Hz, 1H), 8.54 (d, J=2.44 Hz, 1H),12.11 (s, 1H). MS (ESI+) m/z 391.1 (M+H)⁺.

Example 87N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide

Example 87 was obtained as a by-product from the preparation of Example86c. ¹H NMR (500 MHz, DMSO-d₆) 1.93-1.98 (m, 1H), 2.17-2.24 (m, 1H),2.48 (d, J=5.19 Hz, 3H), 3.57 (s, 3H), 3.67-3.78 (m, 3H), 3.91-3.94 (m,1H), 5.65-5.67 (m, 1H), 6.19 (t, J=2.29 Hz, 1H), 7.33 (t, J=2.75 Hz,1H), 7.43 (s, 1H), 7.55 (q, J=4.88 Hz, 1H), 8.06 (d, J=2.44 Hz, 1H),8.51 (d, J=2.44 Hz, 1H), 12.13 (s, 1H). MS (ESI+) m/z 405.1 (M+H)⁺.

Example 886-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one4-bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-oneExample 88a

To a cold (−78° C., dry ice/acetone bath) solution of Example 1e (0.2 g,0.525 mmol) in tetrahydrofuran (6 mL) was added a freshly preparedsolution of lithium di-isopropyl amide (1.2 equivalents). The reactionmixture was stirred at −78° C. for 45 minutes. A solution of iodine(0.054 ml, 1.049 mmol) in tetrahydrofuran (0.5 mL) was added at −78° C.The cooling bath was removed, and the reaction mixture was allowed towarm to room temperature and stirred for 1 hour. The reaction wasquenched by the addition of saturated aqueous sodium thiosulfate (20mL). The reaction mixture was partitioned between water and ethylacetate. The layers were separated, and the aqueous layer was extractedwith additional ethyl acetate. The combined organics were washed withbrine, dried with anhydrous MgSO₄, filtered and concentrated to dryness.The residue was purified by flash chromatography (silica gel, 1-100%ethyl acetate/hexane). The recovered material was further purified byreverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) toafford the title compound (55 mg, 21%).

Example 88b4-bromo-6-methyl-2-phenyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 88a (0.1 g, 0.197 mmol), phenylboronic acid (0.024g, 0.197 mmol), Pd(PPh₃)₄ (0.011 g, 0.0096 mmol), and sodiumhydrogencarbonate (0.041 g, 0.493 mmol) in dimethylformamide (2 mL) andwater (0.6 mL) was heated at 85° C. for 4 hours. After cooling, thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 30% ethyl acetate to afford0.084 g of the title compound.

Example 88c6-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 88c was prepared according to the procedure used for thepreparation of Example 1f, substituting 88b for Example 1e, followed bypurification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFAin water), to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ3.53 (s, 3H), 6.67 (d, J=1.22 Hz, 1H), 6.93 (d, J=7.63 Hz, 2H),7.01-7.04 (m, 2H), 7.26-7.31 (m, 5H), 7.36-7.43 (m, 3H), 7.56 (dd,J=7.48, 1.68 Hz, 1H), 7.89 (d, J=7.32 Hz, 1H), 12.31 (s, 1H). MS (ESI+)m/z 393.3 (M+H)⁺.

Example 89N-{3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-phenoxyphenyl}methanesulfonamide

Example 89 was prepared according to the procedure used for thepreparation of Example 20b, substituting Example 71 for Example 20a, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 3.02 (s, 3H),3.47 (s, 3H), 4.50 (s, 2H), 6.19 (d, J=1.83 Hz, 1H), 6.82 (d, J=7.63 Hz,2H), 6.99 (t, J=7.32 Hz, 1H), 7.05 (d, J=8.85 Hz, 1H), 7.21-7.27 (m,4H), 7.38 (d, J=2.75 Hz, 1H), 9.75 (s, 1H), 11.60 (s, 1H). MS (ESI+) m/z440.1 (M+H)⁺.

Example 90N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 90a 4-(2-bromo-4-nitrophenoxy)benzonitrile

Example 90a was prepared according to the procedure used for thepreparation of Example 7a, substituting 4-hydroxybenzonitrile forphenol, to provide the title compound.

Example 90b 4-(4-amino-2-bromophenoxy)benzonitrile

To a 250 mL stainless steel pressure bottle were added Example 90a (3.21g, 10.1 mmol), platinum (IV) oxide (0.642 g, 2.83 mmol) andtetrahydrofuran (70 mL) under a stream of nitrogen. The reaction flaskwas charged with hydrogen to 30 psi and stirred at ambient temperaturefor 45 minutes. The mixture was filtered through a nylon membrane. Thefiltrate was concentrated. The residue was purified by flashchromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide thetitle compound (1.75 g, 60% yield).

Example 90c4-(4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile

A mixture of example 90b (1.75 g, 6.05 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.07 g,12.1 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante(0.159 g, 0.545 mmol), potassium acetate (1.31 g, 13.3 mmol) andtris(dibenzylideneacetone)dipalladium(0) (0.166 g, 0.182 mmol) indioxane (30 mL) was degassed and backfilled with nitrogen. The reactionmixture was heated at 80° C. for 20 hours and then cooled to ambienttemperature. The mixture was concentrated and the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated and washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, hexane/ethyl acetate) toprovide the title compound (2.0 g, 98% yield).

Example 90d4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)benzonitrile

Example 90d was prepared according to the procedure used for thepreparation of Example 1f, substituting Example 90c for2-phenoxyphenylboronic acid, with purification by preparative HPLC (C18,10-100% acetonitrile in 0.1% TFA in water), to provide the titlecompound.

Example 90eN-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 90e was prepared according to the procedure used for thepreparation of Example 4, Method A, substituting ethanesulfonyl chloridefor methanesulfonyl chloride, and Example 90d for Example 3,respectively, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 12.01-12.05 (m, 1H) 9.94 (s, 1H) 7.62-7.69 (m, 2H) 7.43 (d, J=2.75Hz, 1H) 7.21-7.33 (m, 4H) 6.86-6.93 (m, 2H) 6.22 (dd, J=2.75, 2.14 Hz,1H) 3.46 (s, 3H) 3.16 (q, J=7.32 Hz, 2H) 1.25 (t, J=7.32 Hz, 3H). MS(ESI+) m/z 449.1 (M+H)⁺.

Example 912-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamideExample 91a6-methyl-4-(5-nitro-2-(tetrahydrofuran-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 91a was prepared according to the procedure used for thepreparation of Example 29a, substituting tetrahydrofuran-3-ol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 91b4-(5-amino-2-(tetrahydrofuran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 91b was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 91a for Example 29a, toprovide the title compound.

Example 91c2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide

To a mixture of Example 91b (80.0 mg, 0.246 mmol) and triethylamine(74.6 mg, 0.738 mmol) in dichloromethane (4 mL) was added dropwise2-fluoroethanesulfonyl chloride (144 mg, 0.984 mmol), and the reactionmixture was stirred at about ambient temperature for about 1 hour. Thereaction mixture was neutralized with saturated aqueous ammoniumchloride solution (50 mL) and the mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution, dried (anhydrous magnesiumsulfate), filtered, and concentrated. The residue was purified bypreparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to providethe title compound (7.0 mg, 6.5% yield). ¹H NMR (300 MHz, CDCl₃) □ ppm11.54 (bs, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.19 (s, 1H), 6.88 (d, J=8.7 Hz,1H), 6.73 (d, J=2.7 Hz, 1H) 6.67 (dd, J=3.1, 8.8 Hz, 1H), 6.40 (dd,J=2.0, 2.7 Hz, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.85-3.62 (m, 8H), 2.97(bs, 1H), 2.24-1.85 (m, 2H). MS (ESI+) m/z 436.2 (M+H)⁺.

Example 92N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]propane-1-sulfonamide

Example 92 was prepared according to the procedure used for thepreparation of Example 4, (Method A), substituting Example 91b forExample 3 and substituting propane-1-sulfonyl chloride formethanesulfonyl chloride, to provide the title compound. ¹H NMR (300MHz, CDCl₃) □ ppm 10.63 (bs, 1H), 7.25 (m, 3H), 6.90 (d, J=8.7 Hz, 1H),6.46-6.35 (m, 2H), 4.88 (bs, 1H), 4.01-3.66 (m, 7H), 3.12-3.03 (m, 2H),2.2 (bs, 1H), 2.19-1.80 (m, 4H), 1.06 (t, J=7.4 Hz, 3H). MS (ESI+) m/z432.2 (M+H)⁺.

Example 93N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]propane-1-sulfonamide

Example 93 was prepared according to the procedure used for thepreparation of Example 4, (Method A), substituting Example 33b forExample 3 and substituting propane-1-sulfonyl chloride formethanesulfonyl chloride, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) □□ ppm 12.03 (bs, 1H), 9.91 (s, 1H), 7.70-7.63 (m, 2H),7.42 (d, J=2.5 Hz, 1H), 7.32-7.17 (m, 4H), 6.93-6.86 (m, 2H), 6.22 (dd,J=2.8, 1.9 Hz, 1H), 3.46 (s, 3H), 3.18-3.09 (m, 2H), 1.92-1.65 (m, 2H),0.98 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 463.2 (M+H)⁺.

Example 94N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]propane-1-sulfonamideExample 94a6-methyl-4-(5-nitro-2-(2,4,6-trifluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 94a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2,4,6-trifluorophenol forphenol, to provide the title compound.

Example 94b4-(5-amino-2-(2,4,6-trifluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 94b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 94a for Example 2b, toprovide the title compound.

Example 94cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]propane-1-sulfonamide

Example 94c was prepared according to the procedure used for thepreparation of Example 4, (Method A), substituting Example 94b forExample 3 and substituting propane-1-sulfonyl chloride formethanesulfonyl chloride, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) □ ppm 12.07 (bs, 1H), 9.72 (s, 1H), 7.44-7.33 (m, 2H),7.33-7.28 (m, 3H), 7.14 (dd, J=8.8, 2.7 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H),6.24-6.19 (m, 1H), 3.56 (s, 3H), 3.11 3.02 (m, 2H), 1.78-1.62 (m, 2H),0.95 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 492.1 (M+H)⁺.

Example 953-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzenesulfonamideExample 95a 3-nitro-4-phenoxybenzenesulfonamide

Phenol (1.282 g, 13.63 mmol) in dimethylformamide (20 mL) was treatedwith 60% sodium hydride (0.545 g, 13.63 mmol). The reaction mixture wasstirred for 10 minutes. To this solution was added4-fluoro-3-nitrobenzenesulfonamide (0.75 g, 3.41 mmol). The reactionmixture was stirred at ambient temperature for 2 hours. The reactionmixture was partitioned between water and ethyl acetate. The aqueouslayer was neutralized with 10% HCl and extracted with additional ethylacetate twice. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (1:1 ethyl acetate/hexanes) on silica gel to give 0.96 gof the title product.

Example 95b 3-amino-4-phenoxybenzenesulfonamide

Example 95b was prepared according to the procedure used for thepreparation of Example 29b, substituting 95a for Example 29a, to providethe title compound.

Example 95c 3-iodo-4-phenoxybenzenesulfonamide

Example 95c was prepared according to the procedure used for thepreparation of Example 85c, substituting 95b for Example 85b, to providethe title compound.

Example 95d3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzenesulfonamide

A mixture of Example 6a (0.086 g, 0.20 mmol), Example 95c (0.083 g, 0.22mmol), Pd(PPh₃)₄ (0.012 g, 5 mol %) and cesium fluoride (0.091 g, 0.6mmol) in dimethoxyethane (2 mL) and methanol (1 mL) was heated undermicrowave conditions (110° C., 30 minutes). The reaction mixture wascooled to ambient temperature and portioned between ethyl acetate andwater. The organic layer was separated and dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) toprovide the title compound (48 mg, 61% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 12.08 (s, 1H), 7.95 (d, J=2.14 Hz, 1H), 7.79 (dd, J=8.54, 2.44 Hz,1H), 7.36-7.39 (m, 5H), 7.16 (t, J=7.48 Hz, 1H), 7.03-7.05 (m, 3H), 6.28(t, J=2.29 Hz, 1H), 3.55 (s, 3H). MS (ESI+) m/z 396.2 (M+H)⁺.

Example 966-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 96a 5-bromo-6-(cyclohexylamino)pyridine-3-sulfonamide

A mixture of Example 86a (0.136 g, 0.5 mmol) and cyclohexanamine (0.198g, 2.0 mmol) in dioxane (2 mL) was heated under microwave conditions(140° C., 1 hour). The solvent was removed, and the residue was purifiedby flash chromatography (3:2 ethyl acetate/hexanes) on silica gel togive 0.164 g of the title product.

Example 96b6-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 96b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 96a for Example 95c, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.17 (s,1H), 8.38 (d, J=2.44 Hz, 1H), 7.69 (d, J=2.44 Hz, 1H), 7.32 (t, J=2.75Hz, 1H), 7.29 (s, 1H), 7.18 (br s, 2H), 6.04 (t, J=2.29 Hz, 1H), 5.97(d, J=7.63 Hz, 1H), 3.56 (s, 3H), 1.81-1.82 (m, 2H), 1.54-1.65 (m, 3H),1.01-1.33 (m, 5H) MS (ESI+) m/z 402.1 (M+H)⁺.

Example 976-(cyclohexylamino)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 97 was isolated as a minor product during the preparation ofExample 96b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.16 (s, 1H), 8.35 (d,J=2.44 Hz, 1H), 7.69 (d, J=2.44 Hz, 1H), 7.32 (t, J=2.75 Hz, 1H), 7.29(s, 1H), 7.18 (q, J=4.88 Hz, 1H), 6.02 (t, J=2.29 Hz, 1H), 5.96 (d,J=7.24 Hz, 1H), 3.99-4.05 (m, 1H), 3.55 (s, 3H), 2.42 (d, J=4.88 Hz,3H), 1.80-1.82 (m, 2H), 1.54-1.65 (m, 3H), 1.01-1.33 (m, 6H) MS (ESI+)m/z 416.1 (M+H)⁺.

Example 98N-methyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]sulfuricdiamide

To a mixture of Example 94b (76.3 mg, 0.198 mmol) and triethylamine(60.1 mg, 0.594 mmol) in dichloromethane (4 mL) was added dropwisemethylsulfamoyl chloride (103 mg, 0.792 mmol), and the reaction mixturewas stirred at ambient temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and the residue was mixed withdioxane (5 mL) and 1M aqueous sodium hydroxide (3 mL, 0.2 mmol) andheated at 70° C. for 1 hour. The reaction mixture cooled to ambienttemperate and then neutralized with saturated aqueous ammonium chloride(50 mL) and the aqueous extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried (anhydrous magnesium sulfate), filtered, andconcentrated. The residue was purified by preparative HPLC (C18, 10-80%acetonitrile in 0.1% TFA/water) to provide the title compound (11 mg,11% yield). ¹H NMR (300 MHz, DMSO-d₆) □ ppm 12.04 (bs, 1H), 9.58 (s,1H), 7.43-7.32 (m, 6H), 7.32-7.16 (m, 1H), 7.10 (dd, J=8.8, 2.7 Hz, 1H),6.75 (d, J=8.8 Hz, 1H), 6.23 (t, J=2.3 Hz, 1H), 3.57 (bs, 3H), 2.35 (d,J=4.9 Hz, 3H). ). MS (ESI+) m/z 479.1 (M+H)⁺.

Example 99N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamideExample 99a6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of tetrahydro-2H-pyran-4-ol (231 mg, 2.265 mmol) intetrahydrofuran (10 mL) was added sodium hydride (181 mg, 4.53 mmol)portion wise. After stirring for 10 minutes, Example 2a (500 mg, 1.133mmol) was added. The mixture was heated at 50° C. for 2 hours. Uponcooling, the reaction mixture was quenched with saturated ammoniumchloride solution (10 mL), diluted with 50% aqueous sodium chloride (80mL) and extracted with ethyl acetate (75 mL, 2×50 mL). The combinedorganics were dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel, 0.5-4% methanol in dichloromethane) to provide the titlecompound (220 mg, 52.6% yield).

Example 99b4-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 99b was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 99a for Example 29a, toprovide the title compound.

Example 99cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamide

Example 99c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 99b forExample 3 and propane-1-sulfonyl chloride for methanesulfonyl chloridewith the exception that the reaction mixture was initially stirred for18 hours at ambient temperature and then heated at 50° C. for 1 hour inthe presence of sodium hydroxide, to provide the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 12.00 (s, 1H), 9.50 (s, 1H), 7.24-7.33 (m, 3H),7.14 (s, 2H), 6.19 (t, J=2.37 Hz, 1H), 4.39-4.53 (m, 1H), 3.53-3.68 (m,5H), 3.33-3.45 (m, 2H), 2.96-3.06 (m, 2H), 1.78-1.92 (m, 2H), 1.63-1.78(m, 2H), 1.39-1.54 (m, 2H), 0.95 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 446.1(M+H)⁺.

Example 1002,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide

To a solution of Example 99b (43.2 mg, 0.127 mmol) in dichloromethane (2mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.140mmol) and triethylamine (0.053 mL, 0.382 mmol). The mixture was stirredfor 18 hours at ambient temperature. The reaction mixture wasconcentrated and the residue was purified by flash column chromatography(silica gel, 0.5-5% methanol in dichloromethane) to provide the titlecompound (20.8 mg, 33.7% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.00(s, 1H), 10.16 (s, 1H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 2H), 6.18-6.24(m, 1H), 4.36-4.55 (m, 3H), 3.52-3.68 (m, 5H), 3.33-3.45 (m, 2H),1.79-1.94 (m, 2H), 1.39-1.57 (m, 2H). MS (ESI+) m/z 486.1 (M+H)⁺.

Example 101N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamideExample 101a4-(2-(4,4-difluorocyclohexyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 101a was prepared according to the procedure used for thepreparation of Example 99a, substituting 4,4-difluorocyclohexanol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 101b4-(5-amino-2-(4,4-difluorocyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 101b was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 101a for Example 29a,to provide the title compound.

Example 101cN-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide

Example 101c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 101b forExample 3 and ethanesulfonyl chloride for methanesulfonyl chloride withthe exception that the reaction mixture was initially stirred for 18hours at ambient temperature and then heated at 50° C. for 1 hour in thepresence of sodium hydroxide to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 12.02 (s, 1H), 9.56 (s, 1H), 7.24-7.34 (m, J=4.36Hz, 3H), 7.17 (s, 2H), 6.15-6.23 (m, 1H), 4.48 (s, 1H), 3.49-3.61 (m,3H), 3.05 (q, J=7.27 Hz, 2H), 1.62-1.88 (m, 8H), 1.22 (t, J=7.34 Hz,3H). MS (ESI+) m/z 466.1 (M+H)⁺.

Example 102N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}propane-1-sulfonamide

Example 102 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 101b forExample 3 and propane-1-sulfonyl chloride for methanesulfonyl chloridewith the exception that the reaction mixture was initially stirred for18 hours at ambient temperature and then heated at 50° C. for 1 hour inthe presence of sodium hydroxide, to provide the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 12.02 (s, 1H), 9.54 (s, 1H), 7.25-7.31 (m, 3H),7.17 (s, 2H), 6.14-6.22 (m, 1H), 4.44-4.56 (m, J=2.78 Hz, 1H), 3.51-3.57(m, 3H), 2.96-3.08 (m, 2H), 1.61-1.89 (m, 10H), 0.95 (t, J=7.54 Hz, 3H).MS (ESI+) m/z 480.2 (M+H)⁺.

Example 103N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}-2,2,2-trifluoroethanesulfonamide

Example 103 was prepared according to the procedure used for thepreparation of Example 100, substituting Example 101b for Example 99b,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.00 (s,1H), 10.19 (s, 1H), 7.25-7.32 (m, 3H), 7.19 (s, 2H), 6.17-6.24 (m, 1H),4.36-4.60 (m, 3H), 3.55 (s, 3H), 1.60-1.88 (m, J=4.07 Hz, 8H). MS (ESI+)m/z 520.1 (M+H)⁺.

Example 104N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}-N′-methylsulfuricdiamide

Example 104 was prepared according to the procedure used for thepreparation of Example 100, substituting Example 101b for Example 99band methylsulfamoyl chloride for 2,2,2-trifluoroethanesulfonyl chloride,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.98 (s,1H), 9.41 (s, 1H), 7.21-7.30 (m, 3H), 7.06-7.17 (m, 3H), 6.15-6.24 (m,1H), 4.44 (s, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 1.59-1.86 (m, 8H). MS(ESI+) m/z 467.1 (M+H)⁺.

Example 105N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamideExample 105a6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 105a was prepared according to the procedure used for thepreparation of Example 99a, substituting tetrahydro-2H-pyran-3-ol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 105b4-(5-amino-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 105b was prepared according to the procedure used for thepreparation of Example 29b, substituting Example 105a for Example 29a,to provide the title compound.

Example 105cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide

Example 105c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 105b forExample 3 and ethanesulfonyl chloride for methanesulfonyl chloride withthe exception that the reaction mixture was initially stirred for 18hours at ambient temperature and then heated at 50° C. for 1 hour in thepresence of sodium hydroxide, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 12.02 (s, 1H), 9.53 (s, 1H), 7.37 (s, 1H), 7.27-7.33(m, 2H), 7.09-7.17 (m, 2H), 6.23 (t, J=2.18 Hz, 1H), 4.23-4.34 (m, 1H),3.67 (dd, J=11.70, 2.58 Hz, 1H), 3.37-3.59 (m, 6H), 3.04 (q, J=7.54 Hz,2H), 1.85-2.00 (m, 1H), 1.51-1.73 (m, 2H), 1.33-1.49 (m, 1H), 1.21 (t,J=7.34 Hz, 3H). MS (ESI+) m/z 432.2 (M+H)⁺.

Example 106N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]propane-1-sulfonamide

Example 106 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 105b forExample 3 and propane-1-sulfonyl chloride for methanesulfonyl chloridewith the exception that the reaction mixture was initially stirred for18 hours at ambient temperature and then heated at 50° C. for 1 hour inthe presence of sodium hydroxide, to provide the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 12.02 (s, 1H), 9.52 (s, 1H), 7.37 (s, 1H), 7.30(s, 2H), 7.12 (s, 2H), 6.23 (t, J 2.18 Hz, 1H), 4.22-4.34 (m, 1H), 3.67(dd, J=11.50, 2.78 Hz, 1H), 3.36-3.59 (m, 6H), 2.96-3.07 (m, 2H),1.85-1.99 (m, 1H), 1.52-1.79 (m, 4H), 1.32-1.50 (m, 1H), 0.95 (t, J=7.54Hz, 3H). MS (ESI+) m/z 446.2 (M+H)⁺.

Example 1072,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide

Example 107 was prepared according to the procedure used for thepreparation of Example 100, substituting Example 105b for Example 99b,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.02 (s,1H), 10.17 (s, 1H), 7.38 (s, 1H), 7.26-7.33 (m, 2H), 7.12-7.18 (m,J=1.59 Hz, 2H), 6.26 (t, J=2.38 Hz, 1H), 4.43 (q, J=9.92 Hz, 2H),4.27-4.36 (m, 1H), 3.68 (dd, J=11.50, 2.38 Hz, 1H), 3.39-3.59 (m, 6H),1.86-2.01 (m, 1H), 1.53-1.73 (m, 2H), 1.36-1.49 (m, 1H). MS (ESI+) m/z486.1 (M+H)⁺.

Example 108N-methyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]sulfuricdiamide

Example 108 was prepared according to the procedure used for thepreparation of Example 100, substituting the Example 105b for Example99b and methylsulfamoyl chloride for 2,2,2-trifluoroethanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.99 (s, 1H), 9.38 (s, 1H), 7.33 (s, 1H), 7.26-7.30 (m, J=2.54, 2.54Hz, 2H), 7.05-7.13 (m, 3H), 6.22-6.27 (m, 1H), 4.16-4.27 (m, 1H), 3.65(dd, J=11.53, 2.37 Hz, 1H), 3.37-3.59 (m, 6H), 2.50-2.53 (m, J=1.70 Hz,3H), 1.84-1.96 (m, 1H), 1.50-1.71 (m, 2H), 1.35-1.47 (m, 1H). MS (ESI+)m/z 433.1 (M+H)⁺.

Example 109N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide

Example 109 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 99b forExample 3 and ethanesulfonyl chloride for methanesulfonyl chloride withthe exception that the reaction mixture was initially stirred for 18hours at ambient temperature and then heated at 50° C. for 1 hour in thepresence of sodium hydroxide, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 12.00 (s, 1H), 9.50 (s, 1H), 7.24-7.33 (m, 3H), 7.14(s, 2H), 6.19 (t, J=2.37 Hz, 1H), 4.39-4.53 (m, 1H), 3.53-3.68 (m, 5H),3.33-3.45 (m, 2H), 2.96-3.06 (m, 2H), 1.78-1.92 (m, 2H), 1.63-1.78 (m,2H), 1.39-1.54 (m, 2H), 0.95 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 432.1(M+H)⁺.

Example 110N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamideExample 110a

5-bromo-6-chloro-N,N-dimethylpyridine-3-sulfonamide5-Bromo-6-chloropyridine-3-sulfonyl chloride (1.455 g, 5 mmol) inmethanol (20 mL) was treated with 2.0 N dimethylamine (6.25 mL, 12.50mmol). The reaction mixture was stirred at ambient temperature for 16hours. The solvent was removed, and the solid was washed with waterseveral times. The solid was then purified by chromatography on silicagel eluting with 15% ethyl acetate in hexanes to give 0.8 g of the titlecompound.

Example 110b5-bromo-N,N-dimethyl-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide

Example 110b was prepared according to the procedure used for thepreparation of Example 29a, substituting 110a for Example 2a, andtetrahydrofuran-3-ol for tetrahydro-2H-pyran-4-ol, respectively, toprovide the title compound.

Example 110cN,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide

Example 110c was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 110b for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.11 (s,1H), 8.53 (d, J=2.44 Hz, 1H), 8.00 (d, J=2.44 Hz, 1H), 7.43 (s, 1H),7.32 (d, J=2.75 Hz, 1H), 6.17 (t, J=2.29 Hz, 1H), 5.67 (d, J=1.53 Hz,1H), 3.93 (dd, J=10.38, 4.58 Hz, 1H), 3.78 (d, J=10.07 Hz, 1H),3.68-3.72 (m, 2H), 3.57 (s, 3H), 2.69 (s, 6H), 2.54-2.56 (m, 5H),2.17-2.24 (m, 1H), 1.94-1.98 (m, 1H). MS (ESI+) m/z 419.2 (M+H)⁺.

Example 1115-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamideExample 111a 5-bromo-6-(phenylamino)pyridine-3-sulfonamide

A mixture of Example 86a (0.136 g, 0.5 mmol), aniline (0.186 g, 2.0mmol), and 60% sodium hydride (0.12 g, 3.0 mmol) in dioxane (2 mL) wasstirred and heated at 60° C. for 16 hours. After cooling, the reactionmixture was partitioned between water and ethyl acetate. The aqueouslayer was neutralized with 10% HCl and extracted with additional ethylacetate twice. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography on silica gel (2:3 ethyl acetate/hexanes) to give 0.095 gof the title product.

Example 111b5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamide

Example 111b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 111a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.17 (s,1H), 8.49 (d, J=2.44 Hz, 1H), 8.25 (s, 1H), 7.87 (d, J=2.44 Hz, 1H),7.55 (d, J=7.63 Hz, 2H), 7.42 (s, 1H), 7.24-7.31 (m, 5H), 6.99 (t,J=7.32 Hz, 1H), 6.04 (m, 1H), 3.58 (s, 3H). MS (ESI+) m/z 396.2 (M+H)⁺.

Example 112N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamide

Example 112 was isolated as a minor product during the preparation ofExample 111b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.17 (s, 1H), 8.44 (d,J=2.44 Hz, 1H), 8.31 (s, 1H), 7.78 (d, J=2.44 Hz, 1H), 7.56 (d, J=7.63Hz, 2H), 7.45 (s, 1H), 7.34-7.37 (m, 1H), 7.25-7.30 (m, 3H), 7.00 (t,J=7.32 Hz, 1H), 6.04 (m, 1H), 3.58 (s, 3H), 2.46 (d, J=4.88 Hz, 3H). MS(ESI+) m/z 410.2 (M+H)⁺.

Example 113N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide

Example 33b (50 mg, 0.140 mmol) and triethylamine (42.6 mg, 0.421 mmol)were combined in dichloromethane (4 mL). 2-Fluoroethanesulfonyl chloride(82 mg, 0.561 mmol) was added dropwise and reaction mixture was stirredfor 1 hour at ambient temperature. The reaction mixture was thenextracted with saturated aqueous sodium chloride, separated, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by preparative HPLC (C18, 10-100% acetonitrile/water, 0.1% TFA)to afford the title compound (1.4 mg, 2% yield). ¹H NMR (300 MHz,DMSO-d₆) □□ ppm 11.98-11.92 (m, 1H), 7.62-7.56 (m, 2H), 7.25 (t, J=2.7Hz, 1H), 7.17 (s, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.82-6.70 (m, 4H),6.24-6.13 (m, 1H), 4.19-4.09 (m, 2H), 3.70-3.62 (m, 2H) 3.45 (s, 3H). MS(ESI+) m/z 467.1 (M+H)⁺.

Example 1142-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide

Example 114 was prepared according to the procedure used for thepreparation of Example 91c, substituting Example 94b for Example 91b, toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □□ ppm 12.00-11.94(m, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.27 (m, 2H), 7.25 (s, 1H), 6.69 (d,J=2.5 Hz, 1H), 6.63-6.47 (m, 2H), 6.22 (dd, J=2.8, 2.0 Hz, 1H), 4.08 (q,J=6.3, 5.7, 6.0 Hz, 2H), 3.60 (t, J=6.3, 6.0 Hz, 2H), 3.55 (bs, 3H). MS(ESI+) m/z 496.2 (M+H)⁺.

Example 115N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]propane-1-sulfonamide

Example 115 was prepared according to the procedure used for thepreparation of Example 27c, substituting propane-1-sulfonyl chloride formethanesulfonyl chloride, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) □□ ppm 12.04 (bs, 1H), 9.76 (s, 1H), 7.42-7.26 (m, 4H),7.18 (dd, J=8.8, 2.7 Hz, 1H), 7.13-6.94 (m, 2H), 6.91 (d, J=8.7 Hz, 1H),6.24 (t, J=2.3 Hz, 1H), 3.53 (s, 3H), 3.13-3.04 (m, 2H), 1.79-1.64 (m,2H), 0.96 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 474.1 (M+H)⁺.

Example 1164-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyrimidin-2-yl)benzamide

A solution of Example 50b (24 mg, 0.06 mmol) in a 4 mL vial wasdissolved in anhydrous tetrahydrofuran (1.0 mL), followed by theaddition of 1-chloro-N,N,2-trimethyl-1-propenylamine (65 μL, 0.48 mmol).This was capped and placed to shake for 2 hours at ambient temperature.Then, a solution of pyrimidin-2-amine (9 mg, 0.09 mmol) in anhydroustetrahydrofuran (0.3 mL) was added, followed by a solution of4-(dimethylamino)pyridine (37 mg, 0.3 mmol) in anhydrous tetrahydrofuran(0.5 mL). The mixture was stirred at 60° C. for 16 hours, cooled, andconcentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOHand purified by reverse phase HPLC (10-80% acetonitrile in 0.1% TFAwater). ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) δ ppm 8.73 (d, J=4.88Hz, 2H) 8.09 (d, J=2.44 Hz, 1H) 7.95 (dd, J=8.70, 2.29 Hz, 1H) 7.42-7.48(m, 1H) 7.41 (s, 1H) 7.32-7.38 (m, 2H) 7.27 (t, J=4.88 Hz, 1H) 7.11-7.17(m, 1H) 6.90 (d, J=8.85 Hz, 1H) 6.32 (d, J=2.75 Hz, 1H) 3.60 (s, 3H);(ESI) m/z 474 (M+H)⁺.

Example 1174-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridin-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 117 was prepared according to the procedure used for thepreparation of Example 116, substituting 2,6-dimethoxypyridin-3-aminehydrochloride for pyrimidin-2-amine, to provide the TFA salt of thetitle compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) δ ppm 8.08(d, J=1.53 Hz, 1H) 7.94 (dd, J=8.85, 2.14 Hz, 1H) 7.74-7.78 (m, 1H)7.40-7.47 (m, 1H) 7.38 (s, 1H) 7.28-7.35 (m, 2H) 7.09-7.15 (m, 1H) 6.91(d, J=8.54 Hz, 1H) 6.43 (d, J=8.24 Hz, 1H) 6.29 (d, J=2.75 Hz, 1H) 3.88(d, J=9.46 Hz, 6H) 3.60 (s, 3H); (ESI) m/z 533 (M+H)⁺.

Example 1184-(2,4-difluorophenoxy)-N-(1H-indazol-6-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 118 was prepared according to the procedure used for thepreparation of Example 116, substituting 1H-indazol-6-amine forpyrimidin-2-amine, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆/D₂O, Temp=25° C.) δ ppm 8.22 (s, 1H) 8.12 (d, J=2.44 Hz, 1H)8.02 (s, 1H) 7.97 (dd, J=8.54, 2.44 Hz, 1H) 7.73 (d, J=8.54 Hz, 1H)7.42-7.48 (m, 1H) 7.41 (s, 1H) 7.30-7.38 (m, 3H) 7.11-7.16 (m, 1H) 6.93(d, J=8.54 Hz, 1H) 6.31 (d, J=2.75 Hz, 1H) 3.61 (s, 3H); (ESI) m/z 512(M+H)⁺.

Example 1194-[2-(2,4-difluorophenoxy)-5-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 119 was prepared according to the procedure used for thepreparation of Example 116, substitutingpiperazin-1-yl(pyrrolidin-1-yl)methanone for pyrimidin-2-amine, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) δppm 7.51 (d, J=2.14 Hz, 1H) 7.39-7.46 (m, 2H) 7.35 (s, 1H) 7.32-7.34 (m,J=2.90, 2.90 Hz, 1H) 7.25-7.31 (m, 1H) 7.07-7.13 (m, 1H) 6.87 (d, J=8.54Hz, 1H) 6.28 (d, J=2.75 Hz, 1H) 3.59-3.71 (m, 1H) 3.56-3.58 (m, 4H)3.40-3.55 (m, 2H) 3.18-3.33 (m, J=6.41, 6.41 Hz, 8H) 1.75 (t, J=6.26 Hz,4H); (ESI) m/z 562 (M+H)⁺.

Example 1204-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 120 was prepared according to the procedure used for thepreparation of Example 116, substitutingN¹,N¹-dimethylbenzene-1,4-diamine for pyrimidin-2-amine, to provide theTFA salt of the title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25°C.) δ ppm 8.09 (d, J=2.44 Hz, 1H) 7.94 (dd, J=8.70, 2.29 Hz, 1H) 7.76(d, J=9.16 Hz, 2H) 7.41-7.47 (m, 1H) 7.39 (s, 1H) 7.29-7.36 (m, 2H) 7.26(d, J=8.85 Hz, 2H) 7.10-7.16 (m, 1H) 6.92 (d, J=8.54 Hz, 1H) 6.29 (d,J=3.05 Hz, 1H) 3.60 (s, 3H) 3.06 (s, 6H); (ESI) m/z 515 (M+H)⁺.

Example 1214-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-4-ylmethyl)benzamide

Example 121 was prepared according to the procedure used for thepreparation of Example 116, substituting pyridin-4-ylmethanamine forpyrimidin-2-amine, to provide the TFA salt of the title compound. ¹H NMR(500 MHz, DMSO-d₆/D₂O, Temp=25° C.) δ ppm 8.79 (d, J=6.41 Hz, 2H) 8.05(d, J=2.14 Hz, 1H) 7.87-7.96 (m, 3H) 7.41-7.47 (m, 1H) 7.28-7.38 (m, 3H)7.09-7.16 (m, 1H) 6.91 (d, J=8.54 Hz, 1H) 6.28 (d, J=2.75 Hz, 1H) 4.73(s, 2H) 3.59 (s, 3H); (ESI) m/z 487 (M+H)⁺.

Example 1224-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide

Example 122 was prepared according to the procedure used for thepreparation of Example 116, substituting1-(2-aminoethyl)pyrrolidin-2-one for pyrimidin-2-amine, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) δ ppm 7.91(d, J=2.44 Hz, 1H) 7.77 (dd, J=8.70, 2.29 Hz, 1H) 7.38-7.47 (m, 1H)7.32-7.36 (m, 2H) 7.26-7.31 (m, 1H) 7.07-7.13 (m, 1H) 6.86 (d, J=8.54Hz, 1H) 6.27 (d, J=2.75 Hz, 1H) 3.59 (s, 3H) 3.33-3.46 (m, 6H) 2.19 (t,J=8.09 Hz, 2H) 1.86-1.95 (m, 2H); (ESI) m/z 507 (M+H)⁺.

Example 1234-(2,4-difluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 123 was prepared according to the procedure used for thepreparation of Example 116, substituting 1-amino-2-methylpropan-2-ol forpyrimidin-2-amine, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆/D₂O, Temp=25° C.) δ ppm 7.98 (d, J=2.14 Hz, 1H) 7.85 (dd,J=8.70, 2.29 Hz, 1H) 7.39-7.45 (m, 1H) 7.35 (s, 1H) 7.32 (d, J=3.05 Hz,1H) 7.25-7.31 (m, 1H) 7.07-7.13 (m, 1H) 6.86 (d, J=8.54 Hz, 1H) 6.26 (d,J=2.75 Hz, 1H) 3.58-3.60 (m, 3H) 3.27 (s, 2H) 1.11 (s, 6H); (ESI) m/z468 (M+H)⁺.

Example 1244-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 124 was prepared according to the procedure used for thepreparation of Example 116, substituting2-(5-methoxy-1H-indol-3-yl)ethanamine for pyrimidin-2-amine, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) δ ppm7.93 (d, J=2.14 Hz, 1H) 7.83 (dd, J=8.54, 2.14 Hz, 1H) 7.39-7.45 (m, 1H)7.30-7.33 (m, 2H) 7.26-7.30 (m, 1H) 7.24 (d, J=8.85 Hz, 1H) 7.14 (s, 1H)7.07-7.13 (m, 1H) 7.03 (d, J=2.44 Hz, 1H) 6.86 (d, J=8.54 Hz, 1H) 6.72(dd, J=8.85, 2.44 Hz, 1H) 6.24 (d, J=2.75 Hz, 1H) 3.67 (s, 3H) 3.59 (s,3H) 3.53 (t, J=7.32 Hz, 2H) 2.92 (t, J=7.32 Hz, 2H); (ESI) m/z 569(M+H)⁺.

Example 125N-(3,4-difluorobenzyl)-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 125 was prepared according to the procedure used for thepreparation of Example 116, substituting (3,4-difluorophenyl)methanaminefor pyrimidin-2-amine, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆/D₂O, Temp=25° C.) δ ppm 8.00 (d, J=2.14 Hz, 1H) 7.87 (dd,J=8.54, 2.14 Hz, 1H) 7.26-7.46 (m, 6H) 7.15-7.20 (m, 1H) 7.08-7.13 (m,1H) 6.88 (d, J=8.54 Hz, 1H) 6.26 (d, J=2.75 Hz, 1H) 4.45 (s, 2H) 3.58(s, 3H); (ESI) m/z 522 (M+H)⁺.

Example 1264-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide

Example 126 was prepared according to the procedure used for thepreparation of Example 116, substituting(4-(trifluoromethoxy)phenyl)methanamine for pyrimidin-2-amine, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ppm 8.01 (d, J=2.44 Hz, 1H) 7.88 (dd, J=8.54, 2.14 Hz, 1H) 7.39-7.47 (m,3H) 7.35 (s, 1H) 7.26-7.34 (m, 4H) 7.08-7.14 (m, 1H) 6.88 (d, J=8.54 Hz,1H) 6.26 (d, J=2.75 Hz, 1H) 4.50 (s, 2H) 3.58 (s, 3H); (ESI) m/z 570(M+H)⁺.

Example 1272-{4-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]piperazin-1-yl}-N,N-dimethylacetamide

Example 127 was prepared according to the procedure used for thepreparation of Example 116, substitutingN,N-dimethyl-2-(piperazin-1-yl)acetamide for pyrimidin-2-amine, toprovide the TFA salt of the title compound. ¹H NMR (500 MHz,DMSO-d₆/D₂O, Temp=25° C.) □ ppm 7.56 (d, J=2.14 Hz, 1H) 7.40-7.48 (m,2H) 7.35 (s, 1H) 7.33 (d, J=2.75 Hz, 1H) 7.26-7.32 (m, 1H) 7.08-7.13 (m,1H) 6.88 (d, J=8.24 Hz, 1H) 6.28 (d, J=2.75 Hz, 1H) 4.26 (s, 2H)2.99-3.71 (m, 11H) 2.92 (d, J=5.49 Hz, 6H); (ESI) m/z 550 (M+H)⁺.

Example 1284-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzamide

Example 128 was prepared according to the procedure used for thepreparation of Example 116, substituting pyridin-3-ylmethanamine forpyrimidin-2-amine, to provide the TFA salt of the title compound. ¹H NMR(500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm 8.78 (s, 1H) 8.72 (d, J=5.19Hz, 1H) 8.36 (d, J=7.93 Hz, 1H) 8.01 (d, J=2.14 Hz, 1H) 7.85-7.92 (m,2H) 7.40-7.46 (m, 1H) 7.35 (s, 1H) 7.33 (t, J=3.36 Hz, 1H) 7.27-7.31 (m,1H) 7.09-7.14 (m, 1H) 6.89 (d, J=8.54 Hz, 1H) 6.26 (d, 1H) 4.63 (s, 2H)3.59 (s, 3H); (ESI) m/z 487 (M+H)⁺.

Example 1294-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-2-ylmethyl)benzamide

Example 129 was prepared according to the procedure used for thepreparation of Example 116, substituting pyridin-2-ylmethanamine forpyrimidin-2-amine, to provide the TFA salt of the title compound. ¹H NMR(500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm 8.68 (d, J=5.49 Hz, 1H)8.23-8.29 (m, 1H) 8.04 (d, J=2.44 Hz, 1H) 7.90 (dd, J=8.70, 2.29 Hz, 1H)7.75 (d, J=7.93 Hz, 1H) 7.69-7.73 (m, 1H) 7.39-7.47 (m, 1H) 7.36 (s, 1H)7.33 (d, J=2.75 Hz, 1H) 7.26-7.32 (m, 1H) 7.09-7.15 (m, 1H) 6.90 (d,J=8.85 Hz, 1H) 6.27 (d, J=2.75 Hz, 1H) 4.73 (s, 2H) 3.59 (s, 3H); (ESI)m/z 487 (M+H)⁺.

Example 1304-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(3,4,5-trimethoxybenzyl)benzamide

Example 130 was prepared according to the procedure used for thepreparation of Example 116, substituting(3,4,5-trimethoxyphenyl)methanamine for pyrimidin-2-amine, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm8.00 (d, J=2.14 Hz, 1H) 7.87 (dd, J=8.70, 2.29 Hz, 1H) 7.39-7.45 (m, 1H)7.35 (s, 1H) 7.32 (d, J=2.75 Hz, 1H) 7.26-7.31 (m, 1H) 7.11 (m, 1H) 6.87(d, J=8.54 Hz, 1H) 6.66 (s, 2H) 6.26 (d, J=2.75 Hz, 1H) 4.41 (s, 2H)3.75 (s, 6H) 3.63 (s, 3H) 3.58 (s, 3H); (ESI) m/z 576 (M+H)⁺.

Example 1314-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 131 was prepared according to the procedure used for thepreparation of Example 116, substitutingN¹,N¹-dimethylethane-1,2-diamine for pyrimidin-2-amine, to provide theTFA salt of the title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25°C.) □ ppm 7.97 (d, J=2.14 Hz, 1H) 7.85 (dd, J=8.70, 2.29 Hz, 1H)7.39-7.46 (m, 1H) 7.31-7.35 (m, 2H) 7.25-7.31 (m, 1H) 7.09-7.15 (m, 1H)6.90 (d, J=8.55 Hz, 1H) 6.25 (d, J=2.75 Hz, 1H) 3.62 (t, J=5.95 Hz, 2H)3.59 (s, 3H) 3.26 (t, J=5.95 Hz, 2H) 2.84 (s, 6H); (ESI) m/z 467 (M+H)⁺.

Example 132N-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 132 was prepared according to the procedure used for thepreparation of Example 116, substituting2-(benzo[d][1,3]dioxol-5-yl)ethanamine for pyrimidin-2-amine, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm7.92 (d, J=2.14 Hz, 1H) 7.79 (dd, J=8.70, 2.29 Hz, 1H) 7.39-7.45 (m, 1H)7.31-7.34 (m, 2H) 7.25-7.31 (m, 1H) 7.06-7.14 (m, 1H) 6.80-6.87 (m, 3H)6.70 (d, J=7.02 Hz, 1H) 6.25 (d, J=3.05 Hz, 1H) 5.94 (s, 2H) 3.59 (s,3H) 3.44 (t, J=7.32 Hz, 2H) 2.76 (t, J=7.32 Hz, 2H); (ESI) m/z 544(M+H)⁺.

Example 1334-(2,4-difluorophenoxy)-N-[2-(1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Example 133 was prepared according to the procedure used for thepreparation of Example 116, substituting 2-(1H-indol-3-yl)ethanamine forpyrimidin-2-amine, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆/D₂O, Temp=25° C.) □ ppm 8.65 (t, J=5.49 Hz, 1H) 7.94 (d, J=2.14Hz, 1H) 7.83 (dd, J=8.70, 2.29 Hz, 1H) 7.58 (d, J=7.93 Hz, 1H) 7.39-7.45(m, 1H) 7.36 (d, J=7.93 Hz, 1H) 7.32-7.34 (m, 2H) 7.25-7.31 (m, 1H) 7.18(s, 1H) 7.05-7.13 (m, 2H) 6.98 (t, J=7.32 Hz, 1H) 6.86 (d, J=8.54 Hz,1H) 6.25 (d, J=2.75 Hz, 1H) 3.59 (s, 3H) 3.48-3.58 (m, 2H) 2.96 (t,J=7.48 Hz, 2H); (ESI) m/z 539 (M+H)⁺.

Example 1344-[2-(2,4-difluorophenoxy)-5-{[4-(furan-2-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 134 was prepared according to the procedure used for thepreparation of Example 116, substitutingfuran-2-yl(piperazin-1-yl)methanone for pyrimidin-2-amine, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm7.82 (s, 1H) 7.55 (d, J=2.14 Hz, 1H) 7.39-7.48 (m, 2H) 7.25-7.37 (m, 3H)7.07-7.13 (m, 1H) 7.05 (d, J=3.36 Hz, 1H) 6.88 (d, J=8.24 Hz, 1H) 6.64(dd, J=3.36, 1.83 Hz, 1H) 6.29 (d, J=2.75 Hz, 1H) 3.74-3.89 (m, 4H)3.41-3.70 (m, 7H); (ESI) m/z 559 (M+H)⁺.

Example 135 tert-butyl{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]piperidin-4-yl}carbamate

Example 135 was prepared according to the procedure used for thepreparation of Example 116, substituting tert-butylpiperidin-4-ylcarbamate for pyrimidin-2-amine, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm 7.45 (d,J=1.83 Hz, 1H) 7.36-7.44 (m, 2H) 7.34 (s, 1H) 7.32 (d, J=2.75 Hz, 1H)7.25-7.31 (m, 1H) 7.06-7.13 (m, 1H) 6.86 (d, J=8.54 Hz, 1H) 6.27 (d,J=2.75 Hz, 1H) 4.31 (s, 1H) 3.42-3.69 (m, 5H) 2.85-3.24 (m, 2H) 1.77 (s,2H) 1.21-1.47 (m, 11H); (ESI) m/z 579 (M+H)⁺.

Example 136 tert-butyl4-{[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]amino}piperidine-1-carboxylate

Example 136 was prepared according to the procedure used for thepreparation of Example 116, substituting tert-butyl4-aminopiperidine-1-carboxylate for pyrimidin-2-amine, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆/D₂O, Temp=25° C.) □ ppm 7.95(d, J=2.14 Hz, 1H) 7.83 (dd, J=8.54, 2.14 Hz, 1H) 7.43 (d, J=8.54 Hz,1H) 7.31-7.35 (m, 2H) 7.24-7.51 (m, 1H) 7.10 (d, J=1.83 Hz, 1H) 6.86 (d,J=8.54 Hz, 1H) 6.24 (d, J=2.75 Hz, 1H) 3.87-4.08 (m, 3H) 3.58 (s, 3H)2.91 (d, J=85.75 Hz, 2H) 1.78 (d, 2H) 1.34-1.45 (m, 11H); (ESI) m/z 579(M+H)⁺.

Example 1374-[2-(2,4-difluorophenoxy)-5-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 137 was prepared according to the procedure used for thepreparation of Example 116, substituting 1-(ethylsulfonyl)piperazine forpyrimidin-2-amine, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆/D₂O, Temp=25° C.) H ppm 7.53 (d, J=2.14 Hz, 1H) 7.38-7.47 (m,2H) 7.35 (s, 1H) 7.33 (d, J=3.05 Hz, 1H) 7.26-7.32 (m, 1H) 7.07-7.13 (m,1H) 6.87 (d, J=8.54 Hz, 1H) 6.28 (d, J=2.75 Hz, 1H) 3.43-3.70 (m, 7H)3.25 (s, 4H) 3.07 (q, J=7.43 Hz, 2H) 1.22 (t, J=7.32 Hz, 3H); (ESI) m/z557 (M+H)⁺.

Example 1384-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 138a4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 6a (0.642 g, 1.5 mmol),2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.380 g, 1.500 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.051 g,0.176 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.041 g, 0.045mmol), and potassium phosphate (0.796 g, 3.75 mmol) in dioxane (10 mL)and water (2.500 mL) was degassed and back-filled with nitrogen severaltimes. The reaction was heated at 60° C. for 16 hours. The reactionmixture was partitioned between water and ethyl acetate. The aqueouslayer was extracted with additional ethyl acetate three times. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel eluting with 30% ethyl acetate in hexanes to give the titlecompound (0.63 g, 1.328 mmol, 89% yield).

Example 138b4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 138a (0.05 g, 0.105 mmol), 2,4-difluorophenol(0.016 g, 0.126 mmol), and cesium carbonate (0.069 g, 0.211 mmol) inDMSO (1 mL) was heated at 120° C. for 16 hours. The reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate three times. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by reverse phase Preparative HPLC (10-80%acetonitrile in 0.1% TFA/water) to give the title compound (0.036 g,0.084 mmol, 79% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (s, 1H),7.99 (d, J=2.44 Hz, 1H), 7.86 (dd, J=8.54, 2.44 Hz, 1H), 7.40-7.56 (m,3H), 7.31 (t, J=2.9 Hz, 1H), 7.14-7.20 (m, 1H), 6.98 (d, J=8.54 Hz, 1H),6.28-6.30 (m, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 431.1(M+H)⁺.

Example 1394-[2-(4-chlorobenzoyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 139 was prepared according to the procedure used for thepreparation of Example 95d, substituting(2-bromophenyl)(4-chlorophenyl)methanone for Example 95c, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.96 (s, 1H), 7.86-7.73(m, 1H), 7.55-7.62 (m, 3H), 7.39-7.43 (m, 2H), 7.25-7.29 (m, 2H), 7.21(t, J=2.75 Hz, 1H), 6.88 (s, 1H), 6.05-6.06 (m, 1H), 3.39 (s, 3H). MS(DCI+) m/z 363.0 (M+H)⁺.

Example 1404-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 139 (0.05 g, 0.138 mmol) and sodiumtetrahydroborate (2) (5.21 mg, 0.138 mmol) in tetrahydrofuran (2 mL) washeated at 60° C. for 3 hours. The solvent was removed, and the residuewas purified by reverse phase Preparative HPLC (10-80% acetonitrile in0.1% TFA/water) to give the title compound (0.042 g, 0.115 mmol, 84%yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.70 (s, 1H), 7.56 (d, J=7.63Hz, 1H), 7.35-7.39 (m, 1H), 7.27-7.31 (m, 1H), 7.21-7.23 (m, 4H), 7.00(d, J=8.54 Hz, 2H), 6.79 (s, 1H), 5.94 (t, J=2.29 Hz, 1H), 5.75 (s, 1H),3.47 (s, 3H). MS (DCI+) m/z 365.0 (M+H)⁺.

Example 141N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimidin-5-yloxy)phenyl]ethanesulfonamideExample 141a6-methyl-4-(5-nitro-2-(pyrimidin-5-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 141a was prepared according to the procedure used for thepreparation of Example 2b, substituting pyrimidin-5-ol for phenol, toprovide the title compound.

Example 141b4-(5-amino-2-(pyrimidin-5-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 141b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 141a for Example 2b, toprovide the title compound.

Example 141cN-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimidin-5-yloxy)phenyl]ethanesulfonamide

Example 141c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 141b forExample 3 and substituting ethanesulfonyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm12.03 (bs, 1H), 9.90 (s, 1H), 8.35 (s, 2H), 7.40 (d, J=2.3 Hz, 1H),7.31-7.22 (m, 4H), 6.25-6.20 (m, 1H), 3.49 (s, 3H), 3.17 (q, J=7.3 Hz,2H), 1.24 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 462.2 (M+H)⁺.

Example 142N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-methyl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamideExample 142a6-methyl-4-(2-((1-methyl-1H-pyrazol-5-yl)methoxy)-5-nitrophenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 142a was prepared according to the procedure used for thepreparation of Example 29a, substituting(1-methyl-1H-pyrazol-5-yl)methanol for tetrahydro-2H-pyran-4-ol, toprovide the title compound.

Example 142b4-(5-amino-2-((1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 142b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 142a for Example 2b, toprovide the title compound.

Example 142cN-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-methyl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamide

Example 142c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 142b forExample 3 and substituting ethanesulfonyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm12.01 (bs, 1H), 9.58 (s, 1H), 7.32-7.14 (m, 6H), 6.20 (d, J=1.8 Hz, 1H),6.10 (dd, J=2.8, 1.9 Hz, 1H), 5.10 (s, 2H), 3.63 (s, 3H), 3.50 (s, 3H),3.04 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 442.1(M+H)⁺.

Example 143N-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamideExample 143a4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 143a was prepared according to the procedure used for thepreparation of Example 29a, substituting(1,3-dimethyl-1H-pyrazol-5-yl)methanol for tetrahydro-2H-pyran-4-ol, toprovide the title compound.

Example 143b4-(5-amino-2-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 143b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 143a for Example 2b, toprovide the title compound.

Example 143cN-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide

Example 143c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 143b forExample 3 and substituting ethanesulfonyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm12.04-11.99 (m, 1H), 9.57 (s, 1H), 7.29-7.13 (m, 5H), 6.12-6.07 (m, 1H),5.98 (s, 1H), 5.03 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H), 3.04 (q, J=7.3Hz, 2H), 2.05 (s, 3H), 1.21 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 456.2(M+H)⁺.

Example 144N-[4-(2,2-dimethylpropoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 144a6-methyl-4-(2-(neopentyloxy)-5-nitrophenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 144a was prepared according to the procedure used for thepreparation of Example 29a, substituting 2,2-dimethylpropan-1-ol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 144b4-(5-amino-2-(neopentyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 144b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 144a for Example 2b, toprovide the title compound.

Example 144c

Example 144c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 144b forExample 3 and substituting ethanesulfonyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm12.00 (s, 1H) 9.50 (s, 1H) 7.26-7.33 (m, 3H) 7.15 (dd, J 2.71, 8.82 Hz,1H) 7.06 (d, J=9.16 Hz, 1H) 6.17-6.22 (m, 1H) 3.59 (s, 2H) 3.54 (s, 3H)3.03 (q, J=7.23 Hz, 2H) 1.21 (t, J=7.29 Hz, 3H) 0.84 (s, 9H). MS (ESI+)m/z 416.5 (M−H)⁺.

Example 145N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 145a4-(2-(cyclopropylmethoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 145a was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol, to provide the title compound.

Example 145b4-(5-amino-2-(cyclopropylmethoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 145b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 145a for Example 2b, toprovide the title compound.

Example 145cN-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 145c was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 145b forExample 3 and substituting ethanesulfonyl chloride for methanesulfonylchloride, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm12.02-11.97 (m, 1H), 9.49 (s, 1H), 7.32-7.24 (m, 3H), 7.14 (dd, J=8.7,2.7 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.21-6.16 (m, 1H), 3.80 (d, J=6.7Hz, 2H), 3.56 (s, 3H), 3.02 (q, J=7.3 Hz, 2H), 1.21 (t, J=7.3 Hz, 3H),1.08 (m, 1H), 0.50-0.39 (m, 2H), 0.27-0.18 (m, 2H). MS (ESI+) m/z 402.1(M+H)⁺.

Example 1464-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamideExample 146a 4-(2,4-difluorophenoxy)-3-nitrobenzenesulfonamide

A solution of 2,4-difluorophenol (5.39 g, 41.4 mmol) inN,N-dimethylformamide (34.5 mL) was cooled to 10° C. and treatedportionwise with sodium hydride (1.66 g, 41.4 mmol). After stirring 15minutes, 4-fluoro-3-nitrobenzenesulfonamide (2.28 g, 10.36 mmol) wasadded portionwise. The reaction mixture was stirred at ambienttemperature for 1.5 hours, diluted into ethyl acetate and quenched with0.5 M HCl to pH 6. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide the title compound (3.24 g, 95%).

Example 146b 3-amino-4-(2,4-difluorophenoxy)benzenesulfonamide

Example 146a (3.24 g, 9.81 mmol), iron (2.74 g, 49.1 mmol), and ammoniumchloride (0.787 g, 14.72 mmol) were stirred in a mixture oftetrahydrofuran (21 mL), ethanol (21 mL) and water (7 mL) at 95° C. for3 hours. The mixture was filtered through a nylon membrane andconcentrated. The residue partitioned between ethyl acetate and water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated toprovide the title compound (2.81 g, 95%).

Example 146c 4-(2,4-difluorophenoxy)-3-iodobenzenesulfonamide

To a solution of Example 146b (2.8 g, 9.32 mmol) in dioxane (20 mL) at0° C. was added concentrated hydrochloric acid (40 mL, 9.32 mmol). Themixture was stirred 15 minutes and a solution of sodium nitrite (0.772g, 11.19 mmol) in water (10 mL) was added. The mixture was stirred for 1hour at 0° C. A solution of potassium iodide (3.10 g, 18.7 mmol) inwater (10 mL) was added and stirring was continued 1 hour at ambienttemperature. The mixture was partitioned between ethyl acetate andwater. The organic layer was washed with saturated sodium thiosulfate,water, and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash column chromatography (silica gel, 0-60% ethyl acetate inhexane) to provide the title compound (2.24 g, 58.4% yield).

Example 146d4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

A suspension of Example 146c (111 mg, 0.270 mmol), Example 6a (150 mg,0.351 mmol), tetrakis(triphenylphosphine)palladium (0) (31.2 mg, 0.027mmol) and cesium fluoride (123 mg, 0.810 mmol) in a mixture of 1,2dimethoxyethane (4.6 mL) and methanol (2.3 mL) was heated undermicrowave conditions at 150° C. for 5 minutes. The reaction mixture waspartitioned between ethyl acetate (75 mL) and 50% aqueous sodiumchloride (75 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated. To a solution of the residue indioxane (4 mL) was added a solution of lithium hydroxide hydrate (113mg, 2.7 mmol) in water (1 mL) and the mixture was heated under microwaveconditions at 120° C. for 30 minutes. The reaction mixture waspartitioned between ethyl acetate (75 mL) and water (75 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel, 0.5-10% methanol in dichloromethane) to provide the titlecompound (74 mg, 63.5% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.09 (s,1H), 7.92 (d, J=2.37 Hz, 1H), 7.76 (dd, J=8.82, 2.37 Hz, 1H), 7.43-7.53(m, 1H), 7.28-7.40 (m, 5H), 7.08-7.18 (m, 1H), 6.95 (d, J=8.82 Hz, 1H),6.27 (d, J=2.71 Hz, 1H), 3.58 (s, 3H). MS (ESI+) m/z 432.2 (M+H)⁺.

Example 1474-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 147a 2-bromo-N-cyclohexyl-4-(methylsulfonyl)aniline

A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.05 g, 0.198mmol) and cyclohexanamine (0.059 g, 0.593 mmol) in dioxane (1 mL) in avial was capped and heated at 110° C. for three days. The reactionmixture was partitioned between water and ethyl acetate. The aqueouslayer was extracted with additional ethyl acetate twice. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash column chromatography on silica geleluting with 40% ethyl acetate in hexanes to afford the title compound(0.044 g, 0.132 mmol, 67.0% yield).

Example 147b4-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 147b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 147a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.13 (s,1H), 7.66 (dd, J=8.7, 2.29 Hz, 1H), 7.51 (d, J=2.14 Hz, 1H), 7.30 (t,J=2.75 Hz, 1H), 7.26 (s, 1H), 6.86 (d, J=8.85 Hz, 1H), 6.00-6.01 (m,1H), 4.83 (br, s, 1H), 3.56 (s, 3H), 3.35-3.44 (m, 1H), 1.84-1.87 (m,2H), 1.53-1.62 (m, 3H), 1.27-1.37 (m, 2H), 1.03-1.12 (m, 3H). MS (APCI+)m/z 400.1 (M+H)⁺.

Example 1484-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-oneExample 148a

Example 148a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2-bromo-1-fluoro-4-nitrobenzenefor Example 2a, and 2,4-difluorophenol for phenol, respectively, toprovide the title compound.

Example 148b 3-bromo-4-(2,4-difluorophenoxy)aniline

Example 148b was prepared according to the procedure used for thepreparation of Example 3, substituting Example 148a for Example 2b, toprovide the title compound.

Example 148c4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Example 148c was prepared according to the procedure used for thepreparation of Example 6a, substituting Example 148b for Example 1e, toprovide the title compound.

Example 148d4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

Example 148d was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 80b for Example 95c andExample 148c for Example 6a, respectively, to provide the TFA salt ofthe title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.69 (s, 1H), 7.44(t, J=2.59 Hz, 1H), 7.32-7.37 (m, 2H), 7.16 (d, J=2.75 Hz, 1H),7.05-7.12 (m, 1H), 6.97-7.02 (m, 1H), 6.92 (d, J=8.54 Hz, 1H), 3.37-6.39(m, 1H), 3.70 (s, 3H). MS (ESI+) m/z 369.4 (M+H)⁺.

Example 1494-[2-(2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 149 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-fluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.99 (d, J=2.4 Hz, 1H), 7.89 (dt, J=7.7, 3.9 Hz, 1H),7.50-7.38 (m, 2H), 7.35-7.24 (m, 4H), 6.98 (d, J=8.6 Hz, 1H), 6.32 (d,J=2.8 Hz, 1H), 3.60 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 413 (M+H)⁺.

Example 1504-[2-(3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 150 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-fluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.01 (t, J=3.4 Hz, 1H), 7.93 (dt, J=7.1, 3.5 Hz, 1H),7.47-7.37 (m, 2H), 7.34 (t, J=3.3 Hz, 1H), 7.21 (t, J=6.3 Hz, 1H), 6.96(dddd, J=26.2, 21.5, 8.3, 2.2 Hz, 3H), 6.30 (d, J=2.8 Hz, 1H), 3.57 (s,3H), 3.27 (s, 3H). MS (ESI+) m/z 413 (M+H)⁺.

Example 1514-[2-(4-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 151 was prepared according to the procedure used for thepreparation of Example 138b, substituting 4-fluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.98 (d, J=2.4 Hz, 1H), 7.89 (dd, J=8.7, 2.4 Hz, 1H),7.43 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31-7.22 (m, 2H), 7.22-7.10 (m,2H), 7.04 (d, J=8.7 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.25(s, 3H). MS (ESI+) m/z 413 (M+H)⁺.

Example 1524-[2-(2-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 152 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-chlorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.02 (dd, J=7.0, 1.6 Hz, 1H), 7.96-7.85 (m, 1H),7.65-7.57 (m, 1H), 7.47 (s, 1H), 7.44-7.34 (m, 2H), 7.33-7.21 (m, 2H),6.92 (d, J=8.7 Hz, 1H), 6.37 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.26 (s,3H). MS (ESI+) m/z 429 (M+H)⁺.

Example 1534-[2-(3-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 153 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-chlorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.01 (d, J=2.4 Hz, 1H), 7.99-7.88 (m, 1H), 7.43-7.37(m, 2H), 7.35 (t, J=3.3 Hz, 1H), 7.27-7.19 (m, 2H), 7.16 (dd, J=10.2,8.1 Hz, 1H), 7.08-6.93 (m, 1H), 6.30 (d, J=2.8 Hz, 1H), 3.57 (s, 3H),3.27 (s, 3H). MS (ESI+) m/z 429 (M+H)⁺.

Example 1544-[2-(4-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 154 was prepared according to the procedure used for thepreparation of Example 138b, substituting 4-chlorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.00 (d, J=2.4 Hz, 1H), 7.91 (dd, J=8.3, 2.0 Hz, 1H),7.56-7.38 (m, 3H), 7.34 (t, J=3.3 Hz, 1H), 7.19-7.07 (m, 3H), 6.29 (d,J=2.8 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 429 (M+H)⁺.

Example 1553-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile

Example 155 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-cyanophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.02 (d, J=2.4 Hz, 1H), 7.99-7.91 (m, 1H), 7.68-7.49(m, 3H), 7.46-7.38 (m, 2H), 7.38-7.32 (m, 1H), 7.24 (d, J=8.6 Hz, 1H),6.30 (d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 420(M+H)⁺.

Example 1564-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile

Example 156 was prepared according to the procedure used for thepreparation of Example 138b, substituting 4-cyanophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.05 (d, J=2.4 Hz, 1H), 8.02-7.94 (m, 1H), 7.80-7.73(m, 2H), 7.38 (t, J=4.3 Hz, 2H), 7.33 (t, J=3.3 Hz, 1H), 7.17-7.03 (m,2H), 6.25 (d, J=2.8 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 3H). MS (ESI+) m/z420 (M+H)⁺.

Example 1576-methyl-4-{5-(methylsulfonyl)-2-[3-(trifluoromethyl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 157 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-trifluorormethylphenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.03 (d, J=2.4 Hz, 1H), 7.95 (dd, J=8.6, 2.4 Hz, 1H),7.62-7.56 (m, 1H), 7.54-7.48 (m, 1H), 7.42 (d, J=7.1 Hz, 1H), 7.37-7.31(m, 3H), 7.25 (d, J=8.6 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 3.55 (s, 3H),3.28 (s, 3H). MS (ESI+) m/z 463 (M+H)⁺.

Example 1584-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Cyclopropylmethanol (0.014 g, 0.19 mmol) in tetrahydrofuran (2 mL) wastreated with 60% sodium hydride (10.11 mg, 0.253 mmol). The reactionmixture was stirred at ambient temperature for 5 minutes. To thissolution was added Example 138a (0.03 g, 0.063 mmol). The reactionmixture was heated at 60° C. for 16 hours. The solvent was removed, andthe residue was purified by Preparative HPLC (C18, 10-80% CH₃CN/water(0.1% TFA)) to give the title compound (0.012 g, 0.032 mmol, 51.0%yield). ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.88 (dd, J=8.6, 2.5 Hz,1H), 7.84 (d, J=2.4 Hz, 1H), 7.37 (s, 1H), 7.34 (d, J=2.4 Hz, 2H), 7.32(d, J=3.5 Hz, 2H), 6.17 (d, J=2.8 Hz, 1H), 3.99 (d, J=6.8 Hz, 2H), 3.20(s, 3H), 1.17-1.06 (m, 1H), 0.52-0.41 (m, 2H), 0.34-0.24 (m, 2H). MS(ESI+) m/z 373 (M+H)⁺.

Example 159N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)phenyl]methanesulfonamide

Example 159 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 148d forExample 3, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 12.72 (s, 1H), 9.79 (s, 1H), 7.45 (t, J=2.59 Hz, 1H), 7.40 (t,J=2.44 Hz, 1H), 7.31-7.38 (m, 2H), 7.11-7.17 (m, 1H), 6.89-7.03 (m, 1H),6.39-6.40 (m, 1H), 3.70 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z 447.1(M+H)⁺.

Example 160N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)phenyl]ethanesulfonamide

Example 160 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 148d forExample 3, and ethanesulfonyl chloride for methanesulfonyl chloride,respectively, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 12.72 (s, 1H), 9.86 (s, 1H), 7.45 (t, J=2.75 Hz, 1H), 7.41 (d,J=2.75 Hz, 1H), 7.31-7.40 (m, 2H), 7.10-7.16 (m, 1H), 6.98-7.03 (m, 1H),6.38-6.39 (m, 1H), 3.70 (s, 3H), 3.11 (q, J=7.43 Hz, 2H), 1.23 (t,J=7.32 Hz, 3H). MS (ESI+) m/z 461.1 (M+H)⁺.

Example 1614-[2-(isoquinolin-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 161 was prepared according to the procedure used for thepreparation of Example 138b, substituting isoquinolin-5-ol for2,4-difluorophenol, to provide the TFA salt of the title compound. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm 9.68 (s, 1H), 8.58 (d, J=6.4 Hz, 1H),8.30 (d, J=6.4 Hz, 1H), 8.11 (t, J=4.9 Hz, 2H), 8.00 (dd, J=8.6, 2.4 Hz,1H), 7.78 (t, J=8.1 Hz, 1H), 7.55-7.46 (m, 2H), 7.40 (d, J=8.6 Hz, 1H),7.33 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H), 3.97 (s, 1H), 3.47 (s,3H), 3.31 (s, 3H). MS (ESI+) m/z 445 (M+H)⁺.

Example 1626-methyl-4-[5-(methylsulfonyl)-2-(quinolin-6-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 162 was prepared according to the procedure used for thepreparation of Example 138b, substituting quinolin-6-ol for2,4-difluorophenol, to provide the TFA salt of the title compound. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm 9.03 (dd, J=4.8, 1.4 Hz, 1H), 8.71 (d,J=8.1 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.99 (dd,J=8.6, 2.4 Hz, 1H), 7.88-7.80 (m, 1H), 7.74 (dt, J=3.7, 2.5 Hz, 2H),7.45 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.32 (t, J=3.3 Hz, 1H), 6.34 (d,J=2.8 Hz, 1H), 3.53 (d, J=6.8 Hz, 3H), 3.30 (s, 3H). MS (ESI+) m/z 446(M+H)⁺.

Example 1634-{2-[2-chloro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 163 was prepared according to the procedure used for thepreparation of Example 138b, substituting2-chloro-5-trifluoromethylphenol for 2,4-difluorophenol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 8.03 (d, J=2.4 Hz,1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.58 (dd,J=16.2, 8.4 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.44 (s, 1H), 7.34 (d,J=2.8 Hz, 1H), 7.27-7.13 (m, 2H), 6.33 (d, J=2.9 Hz, 1H), 3.56 (s, 3H),3.28 (s, 3H). MS (ESI+) m/z 496 (M+H)⁺.

Example 1644-{2-[2-fluoro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 164 was prepared according to the procedure used for thepreparation of Example 138b, substituting2-fluoro-5-trifluoromethylphenol for 2,4-difluorophenol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 8.01 (d, J=2.4 Hz,1H), 7.93 (dd, J=8.6, 2.4 Hz, 1H), 7.67-7.55 (m, 3H), 7.43 (s, 1H), 7.34(d, J=2.8 Hz, 1H), 7.23-7.15 (m, 2H), 6.29 (d, J=2.8 Hz, 1H), 3.57 (s,3H), 3.27 (s, 3H). MS (ESI+) m/z 480 (M+H)⁺.

Example 1652-{4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}acetamide

Example 165 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-(4-hydroxyphenyl)acetamidefor 2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H),7.43 (s, 1H), 7.36-7.30 (m, 3H), 7.09-7.00 (m, 3H), 6.31 (d, J=2.8 Hz,1H), 3.59 (s, 3H), 3.39 (s, 2H), 3.24 (s, 3H). MS (ESI+) m/z 452 (M+H)⁺.

Example 1664-[2-(3-aminophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 166 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-aminophenol for2,4-difluorophenol, to provide the TFA salt of the title compound. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm 8.00 (d, J=2.4 Hz, 1H), 7.92 (dd,J=8.6, 2.4 Hz, 1H), 7.40 (s, 1H), 7.36-7.24 (m, 2H), 7.15 (d, J=8.6 Hz,1H), 6.78 (dd, J=8.0, 1.9 Hz, 1H), 6.70-6.62 (m, 2H), 6.27 (d, J=2.8 Hz,1H), 3.96 (s, 1H), 3.58 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 410 (M+H)⁺.

Example 167 6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylamino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 167a N-(2-bromo-4-(methylsulfonyl)phenyl)tetrahydrofuran-3-amine

Example 167a was prepared according to the procedure used for thepreparation of Example 147a, substituting tetrahydrofuran-3-amine forcyclohexanamine, to provide the title compound.

Example 167b6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylamino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 167b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 167a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.12 (s,1H), 7.70 (dd, J=8.7, 2.29 Hz, 1H), 7.54 (d, J=2.44 Hz, 1H), 7.29 (t,J=2.75 Hz, 1H), 7.27 (s, 1H), 6.87 (d, J=8.85 Hz, 1H), 6.00 (t, J=2.29Hz, 1H), 5.25 (br s, 1H), 4.17 (br s, 1H), 3.68 (q, J=7.32, Hz, 2H),3.56 (s, 3H), 3.49 (dd, J=9, 3.51 Hz, 1H), 3.12 (s, 3H), 2.12-2.19 (m,1H), 1.74-1.77 (m, 1H). MS (ESI+) m/z 388.2 (M+H)⁺.

Example 1684-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 168a (3-bromo-4-fluorophenyl)(ethyl)sulfane

A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol) andsodium hydroxide (3.95 mL, 19.73 mmol) in MeOH was stirred at 0° C. for10 minutes. To this solution was added iodoethane (1.803 mL, 22.54mmol). The reaction mixture was stirred at ambient temperature for 6hours. The solvent was removed, and the residue was partitioned betweenwater and ethyl acetate. The aqueous layer was extracted with additionethyl acetate three times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated to give the title compound (4.35 g,18.50 mmol, 98% yield). It was used directly for the next reaction.

Example 168b 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene

Example 168a (4.4 g, 18.71 mmol) in dichloromethane (250 mL) was cooledto 0° C. To this solution was treated with mCPBA (10.15 g, 41.2 mmol)portionwise. The reaction was stirred at ambient temperature for 6hours. The solid from the reaction mixture was removed by filtration.The filtrate was washed with saturated aqueous sodium bicarbonateseveral times. The aqueous layer was then extracted with additionaldichloromethane three times. The combined organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 15% ethyl acetate/hexanes toafford the title compound (4.4 g, 16.47 mmol, 88% yield).

Example 168c4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 168c was prepared according to the procedure used for thepreparation of Example 138a, substituting Example 168b for2-bromo-1-fluoro-4-(methylsulfonyl)benzene, to provide the titlecompound.

Example 168d4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 168d was prepared according to the procedure used for thepreparation of Example 138b, substituting Example 168c for Example 138a,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.31 (s,1H), 7.93 (d, J=2.44 Hz, 1H), 7.83 (dd, J=8.54, 2.44 Hz, 1H), 7.52-7.54(m, 1H), 7.42-7.46 (m, 2H), 7.32 (t, J=2.75 Hz, 1H), 7.16-7.19 (m, 1H),6.99 (d, J=8.54 Hz, 1H), 6.27-6.28 (m, 1H), 3.59 (s, 3H), 3.38 (q,J=7.32, Hz, 2H), 1.15 (t, J=7.32 Hz, 1H). MS (ESI+) m/z 445.2 (M+H)⁺.

Example 1694-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 169 was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168c for Example 138a,and 4,4-difluorocyclohexanol for cyclopropylmethanol, respectively, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.81-7.85 (m, 2H), 7.45 (d, J=8.85 Hz, 1H), 7.33 (s, 1H), 7.29 (t,J=2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.81 (s, 1H), 3.56 (s, 3H), 3.29 (q,J=7.32, Hz, 2H), 1.70-1.87 (m, 8H), 1.14 (t, J=7.32 Hz, 1H). MS (ESI+)m/z 451.2 (M+H)⁺.

Example 1704-{5-(ethylsulfonyl)-2-[(1-methylpiperidin-4-yl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 170 was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168c for Example 138a,and 1-methylpiperidin-4-ol for cyclopropylmethanol, respectively, toprovide the TFA salt of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 12.13 (s, 1H), 7.81-7.87 (m, 2H), 7.46 (d, J=8.85 Hz, 1H), 7.34 (s,1H), 7.32 (t, J=2.75 Hz, 1H), 6.11-6.12 (m, 1H), 4.86 (s, 1H), 3.56 (s,3H), 3.30 (s, 3H), 3.29 (q, J=7.32, Hz, 2H), 3.24-3.29 (m, 1H),3.04-3.10 (m, 1H), 2.25-2.29 (m, 2H), 1.91-2.05 (m, 2H), 1.14 (t, J=7.32Hz, 1H). MS (ESI+) m/z 430.2 (M+H)⁺.

Example 1714-[2-(2,1,3-benzothiadiazol-4-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 171 was prepared according to the procedure used for thepreparation of Example 138b, substituting benzo[c][1,2,5]thiadiazol-5-olfor 2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.04 (d, J=2.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.84(dd, J=8.6, 2.4 Hz, 1H), 7.69 (dd, J=8.8, 7.5 Hz, 1H), 7.50 (s, 1H),7.36 (d, J=7.1 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H),6.49 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.27 (s, 3H). MS (ESI⁺) m/z 453(M+H)⁺.

Example 1724-[2-(isoquinolin-7-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 172 was prepared according to the procedure used for thepreparation of Example 138b, substituting isoquinolin-7-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.65 (s, 1H), 8.39 (s, 1H), 8.24 (d, J=8.9 Hz, 1H),8.16-8.04 (m, 1H), 8.03 (dd, J=8.6, 2.4 Hz, 1H), 7.95-7.76 (m, 2H), 7.47(dd, J=20.3, 11.7 Hz, 2H), 7.31 (t, J=5.9 Hz, 1H), 6.32 (d, J=2.8 Hz,1H), 3.51 (s, 3H), 3.31 (s, 3H). MS (ESI+) m/z 446 (M+H)⁺.

Example 1734-[2-(2,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 173 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2,5-difluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.08-7.98 (m, 1H), 7.97-7.83 (m, 1H), 7.50-7.39 (m,2H), 7.35 (t, J=3.3 Hz, 1H), 7.33-7.21 (m, 1H), 7.20-7.08 (m, 2H), 6.31(d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.25 (d, J=6.7 Hz, 3H) MS (ESI+) m/z431 (M+H)⁺.

Example 1744-[2-(3,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 174 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3,4-difluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.99 (d, J=2.4 Hz, 1H), 7.91 (dd, J=8.6, 2.4 Hz, 1H),7.53-7.40 (m, 2H), 7.34 (d, J=2.8 Hz, 1H), 7.29 (ddd, J=11.4, 6.8, 2.9Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 6.95 (dd, J=8.8, 5.0 Hz, 1H), 6.31 (d,J=2.8 Hz, 1H), 3.58 (s, 3H), 3.25 (s, 3H). MS (ESI+) m/z 431 (M+H)⁺.

Example 1756-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 175 was prepared according to the procedure used for thepreparation of Example 138b, substituting4-hydroxy-2,3-dihydro-1H-inden-1-one for 2,4-difluorophenol, to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 8.02 (d, J=2.4Hz, 1H), 7.92 (dd, J=8.6, 2.4 Hz, 1H), 7.50-7.41 (m, 1H), 7.36 (d, J=2.8Hz, 1H), 7.28 (dd, J=7.3, 1.4 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.32 (d,J=2.8 Hz, 1H), 3.62-3.54 (m, 2H), 3.27 (s, 1H), 2.89-2.82 (m, 1H),2.65-2.59 (m, 1H). MS (ESI+) m/z 449 (M+H)⁺.

Example 1764-[2-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 176 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3,5-difluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.02 (d, J=2.4 Hz, 1H), 7.96 (dd, J=8.6, 2.4 Hz, 1H),7.40 (s, 1H), 7.34 (dd, J=5.7, 2.8 Hz, 2H), 6.98 (tt, J=9.3, 2.3 Hz,1H), 6.83-6.62 (m, 2H), 6.29 (d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.27 (s,3H). MS (ESI+) m/z 431 (M+H)⁺.

Example 1776-methyl-4-[2-(4-methylphenoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 177 was prepared according to the procedure used for thepreparation of Example 138b, substituting 4-methylphenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.96 (d, J=2.4 Hz, 1H), 7.88-7.79 (m, 1H), 7.42 (s,1H), 7.33 (d, J=2.8 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.00 (dd, J=8.6,4.3 Hz, 3H), 6.30 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.24 (s, 3H). MS(ESI+) m/z 409 (M+H)⁺.

Example 1784-[2-(2-methoxyphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 178 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-methoxyphenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.94 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.7, 2.4 Hz, 1H),7.47 (s, 1H), 7.39-7.25 (m, 2H), 7.26-7.13 (m, 2H), 7.03 (td, J=7.6, 1.5Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 3.61 (s, 3H),3.23 (s, 3H). MS (ESI+) m/z 425 (M+H)⁺.

Example 1796-methyl-4-{2-[(2-methylpyridin-3-yl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 179 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-methylpyridin-3-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.38 (d, J=2.1 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.98(dd, J=8.5, 2.4 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.53 (dd, J=8.4, 4.9Hz, 1H), 7.43 (s, 1H), 7.35 (d, J=2.8 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H),6.30 (d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H), 2.41 (s, 3H). MS(ESI+) m/z 410 (M+H)⁺.

Example 1804-{2-[3-(dimethylamino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 180 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-(dimethylamino)phenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H),7.42 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.08 (d,J=8.6 Hz, 1H), 6.68 (dd, J=8.3, 2.4 Hz, 1H), 6.52-6.43 (m, 2H), 6.31 (d,J=2.8 Hz, 1H), 3.58 (s, 3H), 3.24 (s, 3H), 2.90 (s, 6H). MS (ESI+) m/z438 (M+H)⁺.

Example 1816-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 181 was prepared according to the procedure used for thepreparation of Example 138b, substituting5-hydroxy-2,3-dihydro-1H-inden-1-one for 2,4-difluorophenol, to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 8.04 (d, J=2.4Hz, 1H), 7.98 (dd, J=8.6, 2.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.40 (s,1H), 7.34 (dd, J=6.9, 5.8 Hz, 2H), 7.11 (s, 1H), 7.08-6.97 (m, 1H), 6.28(d, J=2.9 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 3H), 3.00 (d, J=5.0 Hz, 2H),2.62-2.58 (m, 2H). MS (ESI+) m/z 449 (M+H)

Example 1826-methyl-4-{5-(methylsulfonyl)-2-[(3-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 182 was prepared according to the procedure used for thepreparation of Example 138b, substituting6-hydroxy-2,3-dihydro-1H-inden-1-one for 2,4-difluorophenol, to providethe title compound ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 8.01 (d, J=2.5Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.42 (d, J=14.0Hz, 2H), 7.34 (d, J=2.8 Hz, 1H), 7.22-7.10 (m, 2H), 6.30 (d, J=2.8 Hz,1H), 3.56 (s, 3H), 3.26 (s, 3H), 3.06 (s, 2H), 2.69 (s, 3H). MS (ESI+)m/z 449 (M+H)⁺.

Example 1832-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile

Example 183 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-cyanophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.06 (d, J=2.4 Hz, 1H), 7.99 (dd, J=8.5, 2.4 Hz, 1H),7.81 (dd, J=7.7, 1.6 Hz, 1H), 7.67-7.59 (m, 1H), 7.41 (s, 1H), 7.39-7.24(m, 3H), 7.09 (d, J=8.4 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 3.56 (s, 3H),3.29 (s, 3H). MS (ESI+) m/z 420 (M+H)⁺.

Example 1844-[2-(3-chloro-2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 184 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-fluoro-3chlorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=8.6, 2.4 Hz, 1H),7.47-7.41 (m, 2H), 7.35 (d, J=2.8 Hz, 1H), 7.28-7.23 (m, 2H), 7.13 (d,J=8.6 Hz, 1H), 6.28 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS(ESI+) m/z 447 (M+H)⁺.

Example 1856-methyl-4-[5-(methylsulfonyl)-2-(naphthalen-1-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 185 was prepared according to the procedure used for thepreparation of Example 138b, substituting naphthalen-1-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.02 (d, J=2.4 Hz, 1H), 7.99 (d, J=8.9 Hz, 2H),7.96-7.87 (m, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.59-7.44 (m, 4H), 7.36-7.28(m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.37 (d, J=2.8 Hz, 1H), 3.58 (s, 3H),3.26 (s, 3H). MS (ESI+) m/z 445 (M+H)⁺.

Example 1864-[2-(2-fluoro-5-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 186 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-fluoro-5methylphenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.98 (d, J=2.4 Hz, 1H), 7.89 (dd, J=8.6, 2.4 Hz, 1H),7.43 (s, 1H), 7.35 (d, J=2.8 Hz, 1H), 7.27 (dd, J=10.9, 8.1 Hz, 1H),7.14-7.06 (m, 2H), 6.98 (d, J=8.6 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 3.60(s, 3H), 3.25 (s, 3H), 2.27 (s, 3H). MS (ESI+) m/z 427 (M+H)⁺.

Example 1874-[2-(5-fluoro-2-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 187 was prepared according to the procedure used for thepreparation of Example 138b, substituting 5-fluoro-2-methylphenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.11-7.96 (m, 1H), 7.91 (dt, J=5.1, 2.8 Hz, 1H), 7.43(s, 1H), 7.38-7.28 (m, 2H), 7.07-6.91 (m, 2H), 6.91-6.81 (m, 1H), 6.31(t, J=3.9 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H), 2.04 (s, 3H). MS (ESI+)m/z 427 (M+H)⁺.

Example 1886-methyl-4-[5-(methylsulfonyl)-2-(quinolin-7-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 188 was prepared according to the procedure used for thepreparation of Example 138b, substituting quinolin-7-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.97 (s, 1H), 8.67 (d, J=8.5 Hz, 1H), 8.12 (dd,J=12.8, 5.7 Hz, 2H), 8.02 (dd, J=8.6, 2.4 Hz, 1H), 7.69 (dd, J=8.3, 4.8Hz, 1H), 7.55-7.41 (m, 4H), 7.32 (d, J=2.8 Hz, 1H), 6.32 (s, 1H), 3.50(d, J=16.9 Hz, 3H), 3.30 (d, J=9.2 Hz, 3H). MS (ESI+) m/z 446 (M+H)⁺.

Example 1894-[2-(4-chloro-3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 189 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-fluoro-4-chlorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.01 (t, J=3.5 Hz, 1H), 7.99-7.90 (m, 1H), 7.68-7.52(m, 1H), 7.40 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.29-7.24 (m, 1H), 7.20(dd, J=10.3, 2.7 Hz, 1H), 7.00-6.86 (m, 1H), 6.29 (t, J=3.4 Hz, 1H),3.57 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 447 (M+H)⁺.

Example 1906-methyl-4-[5-(methylsulfonyl)-2-(pyridin-3-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 190 was prepared according to the procedure used for thepreparation of Example 138b, substituting pyridin-3-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.03 (d, J=2.3 Hz, 1H), 8.01-7.90 (m, 1H), 7.72-7.64(m, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.37-7.30 (m, 1H), 7.30-7.15 (m, 1H),6.36-6.24 (m, 1H), 3.56 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 395 (M+H)⁺.

Example 1914-[2-(2,3-dihydro-1H-inden-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 191 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2,3-dihydro-1H-inden-5-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=8.6, 2.4 Hz, 1H),7.42 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.00 (d,J=8.7 Hz, 2H), 6.98 (d, J=2.2 Hz, 1H), 6.85 (dd, J=8.1, 2.3 Hz, 1H),6.31 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.23 (s, 3H), 2.88-2.79 (m, 4H),2.03 (p, J=7.4 Hz, 2H). MS (ESI+) m/z 435 (M+H)⁺.

Example 1926-methyl-4-{5-(methylsulfonyl)-2-[4-(propan-2-yl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 192 was prepared according to the procedure used for thepreparation of Example 138b, substituting 4-isopropylphenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H),7.42 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.32-7.26 (m, 2H), 7.06-6.98 (m,3H), 6.30 (d, J=2.8 Hz, 1H), 3.58 (s, 3H), 3.24 (s, 3H), 2.89 (p, J=6.9Hz, 1H), 1.19 (d, J=6.9 Hz, 6H) MS (ESI+) m/z 437 (M+H)⁺.

Example 1934-[2-(isoquinolin-8-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 193 was prepared according to the procedure used for thepreparation of Example 138b, substituting isoquinolin-8-ol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.34 (bs, 1H), 8.12 (d, J=2.3 Hz, 1H), 8.05 (dd,J=8.4, 2.4 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.55(d, J=8.5 Hz, 1H), 7.48 (s, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.17-7.11 (m,1H), 6.40 (d, J=2.6 Hz, 1H), 3.44 (s, 3H), 3.32 (s, 3H). MS (ESI+) m/z446 (M+H)⁺.

Example 1946-methyl-4-[5-(methylsulfonyl)-2-(3,4,5-trifluorophenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 194 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3,4,5-trifluorophenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 8.00 (d, J=2.4 Hz, 1H), 7.94 (dd, J=8.6, 2.4 Hz, 1H),7.41 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.18-7.10(m, 2H), 6.31 (d, J=2.8 Hz, 1H), 3.57 (s, 3H), 3.26 (s, 3H). MS (ESI+)m/z 449 (M+H)⁺.

Example 1954-(2-benzylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 195 was prepared according to the procedure used for thepreparation of Example 95d, substituting 1-benzyl-2-bromobenzene forExample 95c, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 12.08 (s, 1H), 7.23-7.34 (m, 5H), 7.16-7.19 (m, 2H), 7.09-7.12 (m,1H), 6.92-6.93 (m, 3H), 5.95 (t, J=2.29 Hz, 1H), 3.89 (s, 2H), 3.47 (s,3H). MS (ESI+) m/z 315.3 (M+H)⁺.

Example 1964-(biphenyl-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 196 was prepared according to the procedure used for thepreparation of Example 95d, substituting biphenyl-2-ylboronic acid forExample 6a and Example 1e for Example 95c, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.88 (s, 1H), 7.44-7.49 (m,4H), 7.18-7.24 (m, 4H), 7.13-7.16 (m, 1H), 7.08 (t, J=2.75 Hz, 1H), 6.93(s, 1H), 5.77-5.78 (m, 1H), 3.38 (s, 3H). MS (ESI+) m/z 301.2 (M+H)⁺.

Example 1974-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 197 was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168c for Example 138a,and 1,4-dioxaspiro[4.5]decan-8-ol for cyclopropylmethanol, respectively,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.79-7.81 (m, 2H), 7.40-7.42 (m, 1H), 7.28-7.34 (m, 2H),6.6.12-6.13 (m, 1H), 4.70-4.73 (m, 1H), 3.79-3.34 (m, 3H), 3.65 (s, 3H),3.26-3.31 (m, 2H), 1.99-2.21 (m, 1H), 1.67-1.99 (m, 2H), 1.48-1.52 (m,3H), 1.14 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 473.2 (M+H)⁺.

Example 1984-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 198 was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168c for Example 138ato provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.04 (s,1H), 7.79-7.82 (m, 2H), 7.37 (s, 1H), 7.29-7.33 (m, 2H), 6.13-6.14 (m,1H), 3.99 (d, J=6.71 Hz, 2H), 3.58 (s, 3H), 3.27 (q, J=7.32 Hz, 2H),1.11-1.14 (m, 4H), 0.45-0.048 (m, 2H), 0.26-0.29 (m, 2H). MS (ESI+) m/z387.2 (M+H)⁺.

Example 1994-{5-(ethylsulfonyl)-2-[(4-oxocyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 197 (0.192 g, 0.406 mmol) was treated with 4.0 N hydrogenchloride in dioxane (1.016 mL, 4.06 mmol), tetrahydrofuran (10 mL), andwater (2 mL). The reaction mixture was heated at 60° C. for 2 hours. Thesolvent was removed, and the residue was purified by reverse phase HPLC(C18, 10-80% CH₃CN/water (0.1% TFA)) to give the title compound (0.154g, 0.359 mmol, 88% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.82-7.86 (m, 2H), 7.51 (d, J=8.85 Hz, 1H), 7.34 (s, 1H), 7.28 (t,J=2.75 Hz, 1H), 6.14 (t, J=2.29 Hz, 1H), 4.97-4.99 (m, 1H), 3.56 (s,3H), 3.30 (q, J=7.32 Hz, 2H), 1.96-2.24 (m, 8H), 1.15 (t, J=7.48 Hz,3H). MS (ESI+) m/z 429.2 (M+H)⁺.

Example 2004-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 200a 2-bromo-N-(cyclopropylmethyl)-4-(ethylsulfonyl)aniline

Example 200a was prepared according to the procedure used for thepreparation of Example 147a, substituting cyclopropylmethanamine forcyclohexanamine, and Example 168b for2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the titlecompound.

Example 200b4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 200b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 200a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.14 (s,1H), 7.62 (dd, J=8.7, 2.29 Hz, 1H), 7.45 (d, J=2.14 Hz, 1H), 7.30 (t,J=2.75 Hz, 1H), 7.26 (s, 1H), 6.86 (J=8.85 Hz, 1H), 6.00-6.01 (m, 1H),5.50 (br s, 1H), 3.56 (s, 3H), 3.16 (q, J=7.12 Hz, 2H), 3.04 (d, J=6.71Hz, 2H), 1.15 (t, J=7.48 Hz, 3H), 0.97-1.04 (m, 1H), 0.36-0.41 (m, 2H),0.14-0.18 (m, 2H). MS (ESI+) m/z 386.2 (M+H)⁺.

Example 2016-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 201a2-bromo-4-(ethylsulfonyl)-N-((tetrahydrofuran-3-yl)methyl)aniline

Example 200a was prepared according to the procedure used for thepreparation of Example 147a, substituting(tetrahydrofuran-3-yl)methanamine for cyclohexanamine, and Example 168bfor 2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the titlecompound.

Example 201b6-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 201b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 201a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (s,1H), 7.67 (dd, J=8.85, 2.44 Hz, 1H), 7.50 (d, J=2.14 Hz, 1H), 7.28 (t,J=2.9 Hz, 1H), 7.23 (s, 1H), 6.84 (J=8.85 Hz, 1H), 5.95-5.97 (m, 1H),5.70 (br s, 1H), 3.55-3.70 (m, 7H), 3.38 (dd, J=8.54, 4.88 Hz, 2H), 3.10(m, 5H), 1.84-1.92 (m, 1H), 1.47-1.55 (m, 1H). MS (ESI+) m/z 402.2(M+H)⁺.

Example 2024-{5-(ethylsulfonyl)-2-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 199 (0.052 g, 0.121 mmol) and sodiumtetrahydroborate (6.89 mg, 0.182 mmol) in tetrahydrofuran (5 mL) washeated at 60° C. for 2 hours. The solvent was removed, and the solid wastreated with MeOH and a couple of drops of TFA. The resulting solutionwas purified by Preparative HPLC (C18, 10-80% CH₃CN/water (0.1% TFA)) togive the title compound (second eluting peak, 0.036 g, 0.084 mmol, 68.9%yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.06 (s, 1H), 7.78-7.82 (m,2H), 7.36-7.38 (m, 2H), 7.30 (t, J=2.75 Hz, 1H), 6.14-6.16 (m, 1H),4.62-4.63 (m, 1H), 3.51-3.58 (m, 5H), 3.25-3.31 (m, 2H), 1.75-1.81 (m,2H), 1.50-1.64 (m, 4H), 1.32-1.40 (m, 2H), 1.14 (t, J=7.32 Hz, 3H). MS(ESI+) m/z 431.2 (M+H)⁺.

Example 2034-{5-(ethylsulfonyl)-2-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one

The title compound (first eluting peak) was isolated as a minor productduring the preparation of Example 202. ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.02 (s, 1H), 7.77-7.81 (m, 2H), 7.40 (d, J=8.54 Hz, 1H), 7.31 (s, 1H),7.28 (t, J=2.75 Hz, 1H), 6.09-6.11 (m, 1H), 4.53-4.55 (m, 1H), 3.56 (s,3H), 3.27 (q, J=7.32 Hz, 2H), 1.95-2.00 (m, 2H), 1.68-1.71 (m, 4H),1.27-1.38 (m, 4H), 1.13 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 431.2 (M+H)⁺.

Example 2044-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-oneExample 204a 2-bromo-1-(cyclopropylmethoxy)-4-(ethylsulfonyl)benzene

Example 204a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168b for Example 138a,to provide the title compound.

Example 204b2-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Example 204b was prepared according to the procedure used for thepreparation of Example 6a, substituting Example 204a for Example 1e, toprovide the title compound.

Example 204c4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

Example 204c was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 80b for Example 95c,and Example 204b for Example 6a, respectively, to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.67 (s, 1H), 7.92 (dd,J=8.85, 2.44 Hz, 1H), 7.83 (d, J=2.44 Hz, 1H), 7.43 (t, J=2.75 Hz, 1H),7.40 (d, J=8.85 Hz, 1H), 6.29-6.30 (m, 1H), 4.02 (d, J=7.02 Hz, 2H),3.80 (s, 3H), 3.29 (q, J=7.12 Hz, 2H), 1.12 (t, J=7.32 Hz, 3H),1.01-1.08 (m, 1H), 0.40-0.45 (m, 2H), 0.21-0.25 (m, 2H). MS (ESI+) m/z388.0 (M+H)⁺.

Example 2056-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 205 was prepared according to the procedure used for thepreparation of Example 158, substituting tetrahydrofuran-3-ol forcyclopropylmethanol, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.03 (s, 1H), 7.85-7.89 (m, 2H), 7.31-7.33 (m, 1H), 7.28(t, J=2.75 Hz, 1H), 6.11-6.12 (m, 1H), 5.17-5.20 (m, 1H), 3.89-3.91 (m,2H), 3.63-3.70 (m, 3H), 3.57 (s, 3H), 3.22 (s, 3H), 2.17-2.26 (m, 1H),1.85-.1.91 (m, 1H). MS (ESI+) m/z 389.1 (M+H)⁺.

Example 2064-{2-[(3-fluorooxetan-3-yl)methoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 206 was prepared according to the procedure used for thepreparation of Example 158, substituting (3-fluorooxetan-3-yl)methanolfor cyclopropylmethanol, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.06 (s, 1H), 7.90-7.93 (m, 2H), 7.42 (d, J=8.54 Hz,1H), 7.37 (s, 1H), 7.30 (t, J=2.75 Hz, 1H), 6.16-6.17 (m, 1H), 4.52-4.64(m, 8H), 3.56 (s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 407.1 (M+H)⁺.

Example 2076-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 207a 5-bromo-6-(cyclopropylmethoxy)pyridine-3-sulfonamide

Example 207a was prepared according to the procedure used for thepreparation of Example 29a, substituting 86a for Example 2a, andcyclopropylmethanol for tetrahydro-2H-pyran-4-ol, to provide the titlecompound.

Example 207b6-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 207b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 207a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.12 (s,1H), 8.52 (d, J=2.44 Hz, 1H), 8.12 (d, J=2.44 Hz, 1H), 7.44-7.45 (m,3H), 7.33 (t, J=2.75 Hz, 1H), 6.22-6.24 (m, 1H), 4.23 (d, J=7.02 Hz,2H), 3.58 (s, 3H), 1.14-1.24 (m, 1H), 0.47-0.52 (m, 2H), 0.29-0.33 (m,2H). MS (ESI+) m/z 374.9 (M+H)⁺.

Example 2086-(cyclopropylmethoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

The title compound was isolated as a minor product during thepreparation of Example 207b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.12 (s,1H), 8.49 (s, 1H), 8.05 (d, J=2.44 Hz, 1H), 7.53 (q, J=4.88 Hz, 1H),7.46 (s, 1H), 7.33 (t, J=2.75 Hz, 1H), 6.21-6.22 (m, 1H), 4.25 (d,J=7.32 Hz, 2H), 3.58 (s, 3H), 2.47 (d, J=4.88 Hz, 3H), 1.14-1.24 (m,1H), 0.47-0.52 (m, 2H), 0.29-0.33 (m, 2H). MS (ESI+) m/z 389.2 (M+H)⁺.

Example 2096-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 209a 5-bromo-6-(cyclopropylmethylamino)pyridine-3-sulfonamide

Example 209a was prepared according to the procedure used for thepreparation of Example 96a, substituting cyclopropylmethanamine forcyclohexanamine, to provide the title compound.

Example 209b6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 209b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 209a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.17 (s,1H), 8.38 (d, J=2.44 Hz, 1H), 7.69 (d, J=2.44 Hz, 1H), 7.32 (t, J=2.75Hz, 1H), 7.30 (s, 1H), 7.18 (br s, 2H), 6.62 (s, 1H), 6.05-6.06 (m, 1H),3.56 (s, 3H), 3.22 (d, J=3.97 Hz, 2H), 1.06-1.10 (m, 1H), 0.34-0.38 (m,2H), 0.15-0.17 (m, 2H). MS (ESI+) m/z 374.2 (M+H)⁺.

Example 2106-[(cyclopropylmethyl)amino]-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

The title compound was isolated as a minor product during thepreparation of Example 209b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.17 (s,1H), 8.35 (d, J=2.44 Hz, 1H), 7.60 (d, J=2.44 Hz, 1H), 7.31-7.32 (m,2H), 7.21 (d, J=4.58 Hz, 1H), 6.55 (s, 1H), 6.04-6.05 (m, 1H), 3.56 (s,3H), 3.22 (d, J=5.19 Hz, 2H), 2.43 (d, J=2.75 Hz, 3H), 1.05-1.12 (m,1H), 0.34-0.39 (m, 2H), 0.15-0.19 (m, 2H). MS (ESI+) m/z 386.7 (M+H)⁺.

Example 2114-{5-(ethylsulfonyl)-2-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 199 (0.052 g, 0.121 mmol) in tetrahydrofuran was treated with3.0 M methylmagnesium bromide in tetrahydrofuran (0.485 mL, 0.485 mmol).The reaction mixture was stirred at ambient temperature for 2 hours. Thesolvent was removed, and the solid was treated with MeOH and a few dropsof TFA. The resulting solution was purified by reverse phase PreparativeHPLC (C18, 10-80% CH₃CN/water (0.1% TFA)) to give the title compound(first eluting peak, 0.018 g, 0.040 mmol, 33.4% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.04 (s, 1H), 7.78-7.80 (m, 2H), 7.38 (d, J=9.77 Hz,1H), 7.33 (s, 1H), 7.29 (t, J=2.75 Hz, 1H), 6.11-6.12 (m, 1H), 4.46-4.49(m, 1H), 3.57 (s, 3H), 3.27 (q, J=7.32 Hz, 2H), 1.39-1.76 (m, 8H), 1.13(t, J=7.32 Hz, 3H), 1.10 (s, 3H). MS (ESI+) m/z 445.1 (M+H)⁺.

Example 2124-{5-(ethylsulfonyl)-2-[(trans-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The title compound (second eluting peak) was isolated as a minor productin the preparation of Example 211. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.04(s, 1H), 7.79-7.81 (m, 2H), 7.37 (d, J=9.46 Hz, 1H), 7.30 (s, 1H), 7.29(t, J=2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.46-4.49 (m, 1H), 3.56 (s, 3H),3.28 (q, J=7.32 Hz, 2H), 1.80-1.86 (m, 2H), 1.54-1.59 (m, 2H), 1.23-1.26(m, 4H), 1.13 (t, J=7.32 Hz, 3H), 0.91 (s, 3H). MS (ESI+) m/z 445.1(M+H)⁺.

Example 2134-[2-(cyclobutyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A 4 mL vial was charged with a stir bar, a solution of Example 138a (30mg, 0.063 mmol) in tetrahydrofuran (1 mL), a solution of cyclobutanol(32 mg, 7 equivalents, 0.46 mmol) in tetrahydrofuran (1 mL) and neatsodium hydride (19 mg, 7 equivalents, 0.46 mmol). The reaction mixturewas stirred at 60° C. for 16 hours. The crude material was filtered,concentrated, and purified by reverse phase HPLC (C18, 10-100%CH₃CN/water (0.1% TFA)) to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.98-7.75 (m, 2H), 7.33 (d, J=1.4 Hz, 2H), 7.16 (d,J=8.7 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.82 (p, J=7.2 Hz, 1H), 3.59 (s,3H), 3.19 (d, J=8.5 Hz, 3H), 2.47-2.38 (m, 2H), 1.96 (p, J=9.6 Hz, 2H),1.81-1.72 (m, 1H), 1.72-1.57 (m, 1H). ). MS (ESI+) m/z 373 (M+H)⁺.

Example 2144-[2-(cyclopentylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 214 was prepared according to the procedure used for thepreparation of Example 213, substituting cyclopentylmethanol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.93-7.81 (m, 2H), 7.40-7.29 (m, 3H), 6.14 (d, J=2.8Hz, 1H), 3.99 (d, J=6.6 Hz, 2H), 3.58 (s, 3H), 3.20 (s, 3H), 2.18 (dt,J=14.6, 7.2 Hz, 1H), 1.59 (dt, J=17.2, 8.5 Hz, 2H), 1.44 (dd, J=10.1,4.8 Hz, 4H), 1.31-1.16 (m, 2H). MS (ESI+) m/z 401 (M+H)⁺.

Example 2154-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 215 was prepared according to the procedure used for thepreparation of Example 213, substituting cyclohexanol for cyclobutanol,to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.85(dt, J=4.1, 2.4 Hz, 2H), 7.35 (dd, J=17.3, 5.9 Hz, 3H), 6.16 (d, J=2.8Hz, 1H), 4.66-4.49 (m, 1H), 3.58 (s, 3H), 3.20 (s, 3H), 1.94-1.79 (m,2H), 1.54 (d, J=5.1 Hz, 2H), 1.50-1.28 (m, 5H), 1.21 (d, J=8.9 Hz, 1H).MS (ESI+) m/z 401 (M+H)⁺.

Example 2164-[2-(cyclopentyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 216 was prepared according to the procedure used for thepreparation of Example 213, substituting cyclopentanol for cyclobutanol,to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.88(dd, J=8.7, 2.5 Hz, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.32 (dd, J=10.3, 7.4Hz, 3H), 6.10 (d, J=2.8 Hz, 1H), 4.96 (dt, J=8.3, 2.8 Hz, 1H), 3.58 (s,3H), 3.19 (d, J=8.6 Hz, 3H), 2.53 (dd, J=3.5, 1.7 Hz, 2H), 1.98-1.82 (m,2H), 1.69-1.56 (m, 2H), 1.56-1.46 (m, 4H) MS (ESI+) m/z 387 (M+H)⁺.

Example 2176-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 217 was prepared according to the procedure used for thepreparation of Example 213, substituting (tetrahydrofuran-3-yl)methanolfor cyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.90 (dd, J=8.6, 2.5 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H),7.37 (d, J=8.7 Hz, 1H), 7.33 (d, J=2.8 Hz, 2H), 6.14 (d, J=2.8 Hz, 1H),4.10 (dd, J=9.4, 6.2 Hz, 1H), 4.03 (dd, J=9.4, 7.5 Hz, 1H), 3.58 (s,5H), 3.62-3.52 (m, 6H), 3.40 (dd, J=8.6, 5.8 Hz, 1H), 3.20 (s, 3H),1.93-1.80 (m, 1H), 1.63-1.51 (m, 1H). MS (ESI+) m/z 403 (M+H)⁺.

Example 2186-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxoimidazolidin-1-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 218 was prepared according to the procedure used for thepreparation of Example 213, substituting1-(2-hydroxyethyl)imidazolidin-2-one for cyclobutanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.90 (dd, J=8.6, 2.4Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.34 (d, J=2.8Hz, 2H), 6.15 (d, J=2.8 Hz, 1H), 4.20 (t, J=5.2 Hz, 2H), 3.58 (s, 3H),3.35 (t, J=5.2 Hz, 2H), 3.21 (s, 3H), 3.07 (s, 4H). MS (ESI+) m/z 431(M+H)⁺.

Example 2194-[2-(2-cyclopropylethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 219 was prepared according to the procedure used for thepreparation of Example 213, substituting 2-cyclopropylethanol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.93 (dd, J=8.6, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H),7.43-7.32 (m, 3H), 6.14 (d, J=2.8 Hz, 1H), 4.18 (t, J=6.3 Hz, 2H), 3.23(s, 3H), 1.54 (q, J=6.5 Hz, 2H), 0.72-0.60 (m, 1H), 0.39-0.29 (m, 2H) MS(ESI+) m/z 387 (M+H)⁺.

Example 2204-[2-(cycloheptyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 220 was prepared according to the procedure used for thepreparation of Example 213, substituting cycloheptanol for cyclobutanol,to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm7.91-7.80 (m, 2H), 7.32 (d, J=2.8 Hz, 2H), 7.34-7.27 (m, 3H), 6.14 (d,J=2.8 Hz, 1H), 4.77-4.67 (m, 1H), 3.20 (s, 3H), 1.98-1.84 (m, 2H),1.69-1.57 (m, 2H), 1.57-1.30 (m, 8H). MS (ESI+) m/z 415 (M+H)⁺.

Example 2216-methyl-4-[2-(2-methylpropoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 221 was prepared according to the procedure used for thepreparation of Example 213, substituting 2-methylpropan-1-ol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.92-7.82 (m, 2H), 7.38-7.32 (m, 3H), 7.32 (d, J=2.8Hz, 2H), 6.13 (d, J=2.8 Hz, 1H), 3.88 (d, J=6.3 Hz, 2H), 3.20 (s, 3H),0.83 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 375 (M+H)⁺.

Example 2226-methyl-4-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 222 was prepared according to the procedure used for thepreparation of Example 213, substituting(S)-(1-methylpyrrolidin-2-yl)methanol for cyclobutanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.96 (dd, J=8.6, 2.4Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.43-7.33 (m, 3H), 6.20 (d, J=2.8 Hz,1H), 4.49 (dd, J=11.0, 3.3 Hz, 1H), 4.27 (dd, J=10.9, 8.2 Hz, 1H), 3.59(s, 3H), 3.44-3.34 (m, 1H), 3.25-3.16 (m, 3H), 3.07-2.95 (m, 1H),2.32-2.09 (m, 1H), 2.01-1.83 (m, 1H), 1.85-1.62 (m, 2H). MS (ESI+) m/z416 (M+H)⁺.

Example 2236-methyl-4-{2-[(2-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 223 was prepared according to the procedure used for thepreparation of Example 213, substituting (2-methylcyclopropyl)methanolfor cyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.94-7.79 (m, 2H), 7.41-7.28 (m, 3H), 6.16 (t, J=3.0Hz, 1H), 4.10-3.97 (m, 1H), 3.91 (dd, J=10.3, 7.3 Hz, 1H), 3.59 (d,J=2.7 Hz, 3H), 3.19 (s, 3H), 0.91 (t, J=11.4 Hz, 3H), 0.89-0.75 (m, 1H),0.77-0.63 (m, 1H), 0.48-0.36 (m, 1H), 0.29-0.19 (m, 1H). MS (ESI+) m/z387 (M+H)⁺.

Example 2244-[2-(cyclohexylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 224 was prepared according to the procedure used for thepreparation of Example 213, substituting cyclohexylmethanol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.91-7.82 (m, 2H), 7.38-7.30 (m, 3H), 6.14 (d, J=2.8Hz, 1H), 3.91 (d, J=5.7 Hz, 2H), 3.58 (s, 3H), 3.20 (s, 3H), 1.65-1.57(m, 5H), 1.28-0.85 (m, 5H). MS (ESI+) m/z 415 (M+H)⁺.

Example 2256-methyl-4-{2-[2-(1-methylpyrrolidin-2-yl)ethoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 225 was prepared according to the procedure used for thepreparation of Example 213, substituting2-(1-methylpyrrolidin-2-yl)ethanol for cyclobutanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.93 (dd, J=8.7, 2.4Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.36 (dd, J=10.4, 7.7 Hz, 3H), 6.15 (d,J=2.8 Hz, 1H), 4.30-4.12 (m, 2H), 3.59 (s, 3H), 3.57-3.42 (m, 1H), 3.19(d, J=14.3 Hz, 3H), 3.04 (dt, J=9.9, 5.0 Hz, 1H), 2.93 (dt, J=11.5, 8.5Hz, 1H), 2.53 (dt, J=3.5, 1.7 Hz, 2H), 2.34-2.19 (m, 1H), 2.06 (dtd,J=12.9, 8.1, 5.0 Hz, 1H), 1.96-1.72 (m, 3H), 1.51 (ddd, J=16.7, 13.2,9.3 Hz, 1H). MS (ESI+) m/z 430 (M+H)⁺.

Example 2266-methyl-4-[5-(methylsulfonyl)-2-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 226 was prepared according to the procedure used for thepreparation of Example 213, substituting(R)-5-(hydroxymethyl)pyrrolidin-2-one for cyclobutanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.91 (dd, J=8.7, 2.4Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.42-7.29 (m, 3H), 6.15 (d, J=2.8 Hz,1H), 4.08 (qd, J=9.9, 4.2 Hz, 2H), 3.81 (dt, J=28.2, 14.1 Hz, 1H), 3.58(s, 3H), 3.19 (d, J=11.5 Hz, 3H), 2.09-1.87 (m, 2H), 1.86-1.66 (m, 2H).MS (ESI+) m/z 416 (M+H)⁺.

Example 2276-methyl-4-{5-(methylsulfonyl)-2-[2-(morpholin-4-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 227 was prepared according to the procedure used for thepreparation of Example 213, substituting 2-morpholinoethanol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.97 (dd, J=8.6, 2.4 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H),7.42 (d, J=8.7 Hz, 1H), 7.35 (d, J=2.8 Hz, 2H), 6.12 (d, J=2.8 Hz, 1H),4.48 (t, J=4.6 Hz, 2H), 3.96 (s, 1H), 3.59 (s, 3H), 3.57-3.36 (m, 3H),3.22 (s, 3H), 3.18 (s, 1H), 3.10-2.68 (m, 2H). MS (ESI+) m/z 432 (M+H)⁺.

Example 2286-methyl-4-[5-(methylsulfonyl)-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 228 was prepared according to the procedure used for thepreparation of Example 213, substituting(S)-5-(hydroxymethyl)pyrrolidin-2-one for cyclobutanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.88 (tt, J=15.3,7.7 Hz, 2H), 7.46-7.27 (m, 3H), 6.15 (d, J=2.8 Hz, 1H), 4.08 (qd, J=9.9,4.2 Hz, 2H), 3.83 (dd, J=8.1, 4.1 Hz, 1H), 3.57 (d, J=9.0 Hz, 3H), 3.20(s, 3H), 2.09-1.90 (m, 2H), 1.85-1.69 (m, 2H) MS (ESI+) m/z 416 (M+H)⁺.

Example 2294-{2-[(1-tert-butoxypropan-2-yl)oxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 229 was prepared according to the procedure used for thepreparation of Example 213, substituting 1-tert-butoxypropan-2-ol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.92-7.80 (m, 2H), 7.45-7.24 (m, 3H), 6.19 (d, J=2.8Hz, 1H), 4.74-4.62 (m, 1H), 3.58 (s, 3H), 3.38 (t, J=7.6 Hz, 2H), 3.19(d, J=8.9 Hz, 3H), 1.20 (t, J=8.9 Hz, 3H), 1.02 (s, 9H). MS (ESI+) m/z433 (M+H)⁺.

Example 230 4-{2-[(1S,4R)-bicyclo[2.2.1]hept-2-ylmethoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 230 was prepared according to the procedure used for thepreparation of Example 213, substituting(1S,4R)-bicyclo[2.2.1]heptan-2-ylmethanol for cyclobutanol, to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.92-7.81 (m,2H), 7.43-7.28 (m, 3H), 6.14 (dd, J=8.3, 2.8 Hz, 1H), 4.15-4.07 (m, 1H),4.01-3.78 (m, 2H), 3.20 (s, 3H), 2.18-2.00 (m, 2H), 1.50-1.34 (m, 2H),1.32-1.15 (m, 3H), 1.14-0.95 (m, 2H). MS (ESI+) m/z 427 (M+H)⁺.

Example 2316-methyl-4-{2-[(1-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 231 was prepared according to the procedure used for thepreparation of Example 213, substituting (1-methylcyclopropyl)methanolfor cyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.90-7.83 (m, 2H), 7.33 (d, J=2.9 Hz, 1H), 7.30 (d,J=8.9 Hz, 1H), 6.17 (d, J=2.8 Hz, 1H), 3.90 (s, 2H), 3.19 (s, 3H), 0.97(s, 3H), 0.48-0.41 (m, 2H), 0.31-0.25 (m, 2H). MS (ESI+) m/z 387 (M+H)⁺.

Example 2326-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 232 was prepared according to the procedure used for thepreparation of Example 213, substituting1-(2-hydroxyethyl)pyrrolidin-2-one for cyclobutanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm 7.91 (dd, J=8.6, 2.4Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.41-7.30 (m, 3H), 6.10 (d, J=2.8 Hz,1H), 4.21 (t, J=5.2 Hz, 2H), 3.58 (s, 3H), 3.45 (t, J=5.2 Hz, 2H),3.23-3.16 (m, 3H), 3.01 (t, J=7.0 Hz, 2H), 2.08 (t, J=8.0 Hz, 2H), 1.67(p, J=7.5 Hz, 2H). MS (ESI+) m/z 430 (M+H)⁺.

Example 2336-methyl-4-{2-[(4-methylcyclohexyl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 233 was prepared according to the procedure used for thepreparation of Example 213, substituting 4-methylcyclohexanol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.89-7.83 (m, 2H), 7.39-7.31 (m, 3H), 6.17 (d, J=2.8Hz, 1H), 4.78-4.71 (m, 1H), 3.20 (s, 3H), 1.86-1.75 (m, 2H), 1.57-1.45(m, 2H), 1.41-1.22 (m, 3H), 0.96-0.82 (m, 2H), 0.68 (d, J=6.2 Hz, 3H).MS (ESI+) m/z 415 (M+H)⁺.

Example 2344-[2-(cyclobutylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 234 was prepared according to the procedure used for thepreparation of Example 213, substituting cyclobutylmethanol forcyclobutanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.94-7.80 (m, 2H), 7.34 (dd, J=13.2, 5.7 Hz, 3H),6.14 (d, J=2.8 Hz, 1H), 4.07 (d, J=6.2 Hz, 2H), 3.57 (s, 3H), 3.19 (d,J=9.2 Hz, 3H), 2.61 (d, J=7.1 Hz, 1H), 1.99-1.62 (m, 6H). MS (ESI+) m/z387 (M+H)⁺.

Example 235N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]cyclopropanesulfonamide

Example 235 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 27c forExample 3, and cyclopropanesulfonyl chloride for methanesulfonylchloride, respectively, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.05 (s, 1H), 9.70 (s, 1H), 7.35-7.38 (m, 2H), 7.29-7.30(m, 2H), 7.22 (dd, J=8.7, 2.59 Hz, 1H), 7.06-7.10 (m, 1H), 6.98-7.01 (m,1H), 6.92 (d, J=8.54 Hz, 1H), 6.25-6.26 (m, 1H), 3.54 (s, 3H), 2.61-2.66(m, 1H), 0.90-0.98 (m, 4H). MS (ESI+) m/z 472.1 (M+H)⁺.

Example 236N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-methoxyethanesulfonamide

Example 236 was prepared according to the procedure used for thepreparation of Example 4, Method A, substituting Example 27b for Example3, and 2-methoxyethanesulfonyl chloride for methanesulfonyl chloride,respectively, to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 12.05 (s, 1H), 9.76 (s, 1H), 7.34-7.39 (m, 2H), 7.28-7.30 (m, 2H),7.19 (dd, J=8.85, 2.75 Hz, 1H), 7.05-7.10 (m, 1H), 6.98-7.01 (m, 1H),6.91 (d, J=8.54 Hz, 1H), 6.25-6.26 (m, 1H), 3.68 (t, J=6.1 Hz, 2H), 3.53(s, 3H), 3.37 (t, J=6.1 Hz, 2H), 3.20 (s, 3H). MS (ESI+) m/z 490.1(M+H)⁺.

Example 2376-methyl-4-{5-(methylsulfonyl)-2-[tricyclo[3.3.1.1^(3,7)]dec-2-yloxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 237 was prepared according to the procedure used for thepreparation of Example 158, substituting 2-adamantanol forcyclopropylmethanol, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.04 (s, 1H), 7.88 (d, J=2.44 Hz, 1H), 7.83 (dd, J=8.85,2.44, HZ, 1H), 7.38 (s, 1H), 7.36 (d, J=8.85 Hz, 1H), 7.29 (t, J=2.75Hz, 1H), 6.18-6.19 (m, 1H), 4.70 (s, 1H), 3.56 (s, 3H), 3.21 (s, 3H),2.06 (s, 2H), 1.80 (s, 5H), 1.62-1.65 (m, 5H), 1.34 (d, J=11.29 Hz, 2H).MS (ESI+) m/z 453.2 (M+H)⁺.

Example 2384-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamideExample 238a 3-bromo-4-(cyclopropylmethylamino)benzenesulfonamide

Example 238a was prepared according to the procedure used for thepreparation of Example 96a, substituting cyclopropylmethanamine forcyclohexanamine, and 3-bromo-4-fluorobenzenesulfonamide for Example 86a,respectively, to provide the title compound.

Example 238b4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

Example 238b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 238a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.13 (s,1H), 7.61-7.63 (m, 1H), 7.50 (d, J=2.14 Hz, 1H), 7.30 (t, J=2.75 Hz,1H), 7.20 (s, 1H), 6.97 (br s, 2H), 6.80 (d, J=8.85 Hz, 1H), 6.01 (s,1H), 3.56 (s, 3H), 3.02 (d, J=6.71 Hz, 2H), 0.97-1.03 (m, 1H), 0.35-0.39(m, 2H), 0.13-0.16 (m, 2H). MS (ESI+) m/z 373.2 (M+H)⁺.

Example 2394-[(cyclopropylmethyl)amino]-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

The title compound was isolated as a minor product in the preparation ofExample 238b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.13 (s, 1H), 7.56 (dd,J=8.54, 2.44 Hz, 1H), 7.42 (d, J=2.14 Hz, 1H), 7.23 (s, 1H), 7.30 (t,J=2.75 Hz, 1H), 7.02 (d, J=4.88 Hz, 1H), 6.83 (d, J=8.54 Hz, 1H),6.00-6.01 (m, 1H), 3.56 (s, 3H), 3.02 (d, J=6.71 Hz, 2H), 2.38 (d,J=4.58 Hz, 3H), 0.99-1.18 (m, 1H), 0.36-0.40 (m, 2H), 0.13-0.17 (m, 2H).MS (ESI+) m/z 387.2 (M+H)⁺.

Example 2404-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 240a2-bromo-1-((2,2-difluorocyclopropyl)methoxy)-4-(ethylsulfonyl)benzene

Example 240a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168b for Example 138a,and (2,2-difluorocyclopropyl)methanol for cyclopropylmethanol, toprovide the title compound.

Example 240b4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 240b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 240a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.81-7.85 (m, 2H), 7.37-7.39 (m, 2H), 7.29 (t, J=2.75 Hz, 1H),6.14-6.15 (m, 1H), 4.25-4.29 (m, 2H), 4.16-4.20 (m, 2H), 3.57 (s, 3H),3.29 (q, J=7.43 Hz, 2H), 2.08-2.16 (m, 1H), 1.63-1.66 (m, 1H), 1.44-1.46(m, 1H), 1.13 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 423.1 (M+H)⁺.

Example 2414-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 241a4-(4-bromo-2-methoxyphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

The product from Example 6a (0.2 g, 0.467 mmol),4-bromo-1-iodo-2-methoxybenzene (0.16 g, 0.514 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.014 g,0.047 mmol) and potassium phosphate tribasic (0.347 g, 1.634 mmol) werecombined and sparged with argon for 15 minutes. Meanwhile a solution of4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes andtransferred by syringe into the reaction vessel under argon. The mixturewas stirred at ambient temperature for 20 minutes and partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium chloride, dried (Na₂SO₄), treated with3-mercaptopropyl functionalized silica gel for twenty minutes, filtered,and concentrated. Purification by chromatography (silica gel, 10-80%ethyl acetate in heptanes) afforded the title compound (0.2 g, 88%)

Example 241b4-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The product from Example 241a (0.2 g, 0.410 mmol), potassium hydroxide(0.460 g, 8.21 mmol) and cetyltrimethylammonium bromide (7.48 mg, 0.021mmol) were combined in dioxane (8 mL) and water (4 mL) and heated at100° C. for 18 hours. The reaction mixture was partitioned between equalvolumes of ethyl acetate and water and the pH was adjusted to pH 7 bycareful addition of concentrated HCl. The organic layer was separatedand washed three times with saturated aqueous sodium chloride, dried(Na₂SO₄), filtered, and concentrated. Purification by trituration indichloromethane afforded the title compound (0.1 g, 73%). ¹H NMR (300MHz, DMSO-d₆) δ ppm 11.97 (s, 1H) 7.05-7.42 (m, 5H) 5.87-6.09 (m, 1H)3.75 (s, 3H) 3.54 (s, 3H). MS (ESI+) m/z 333/335 (M+H)⁺.

Example 2426-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 242a 5-bromo-6-(2,4-difluorophenoxy)pyridine-3-sulfonamide

A mixture of Example 86a (0.543 g, 2 mmol), 2,4-difluorophenol (0.390 g,3.00 mmol), and cesium carbonate (1.955 g, 6.00 mmol) in DMSO (10 mL)was heated at 110° C. for 16 hours. After cooling, the reaction mixturewas partitioned between water and ethyl acetate. The aqueous layer wasneutralized with 10% HCl and extracted with additional ethyl acetatetwice. The combined organic layers were washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (3:2ethyl acetate/hexanes) on silica gel to give the title compound (0.53 g,1.451 mmol, 72.6% yield).

Example 242b6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 242b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 242a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.19 (s,1H), 8.46 (d, J=2.44 Hz, 1H), 8.29 (d, J=2.14 Hz, 1H), 7.56 (s, 2H),7.54 (s, 1H), 7.44-7.50 (m, 2H), 7.35 (t, J=2.75 Hz, 1H), 7.14-7.18 (m,1H), 6.34 (t, J=2.44 Hz, 1H), 3.61 (s, 3H). MS (ESI+) m/z 433.2 (M+H)⁺.

Example 2434-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 243a (3-bromo-4-fluorophenyl)(trifluoromethyl)sulfane

3-Bromo-4-fluorobenzenethiol (2.071 g, 10 mmol) in dimethylformamide (10mL) was treated with 60% sodium hydride (0.480 g, 12.00 mmol). Thesolution was stirred for 10 minutes at room temperature.Trifluoroiodomethane (2.74 g, 14.00 mmol) was released into a balloonwith a three-way stopcock. The balloon was then put onto the flask andtrifluoroiodomethane was released into the reaction. After 1 hour, allthe content in the balloon was gone. And the balloon was filled with2.74 g of trifluoroiodomethane again. The reaction mixture was stirredfor 16 hours. The reaction mixture was poured into water, and extractedwith ethyl acetate several times. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The resulting oil wasused directly in the next reaction.

Example 243b 2-bromo-1-fluoro-4-(trifluoromethylsulfonyl)benzene

Example 243a (2.75 g, 10.00 mmol) in acetonitrile (4 mL), carbontetrachloride (4.00 mL), and water (16.00 mL) was treated with sodiumperiodate (6.42 g, 30.0 mmol) and ruthenium(III) chloride hydrate (0.023g, 0.100 mmol). The reaction mixture was stirred at ambient temperaturefor 16 hours. Dichloromethane (100 mL) was added to the reactionmixture, which was then filtered through a pad of filtering agent. Thefiltrate was treated with saturated sodium bicarbonate (50 mL). And theorganic layer was separated. The aqueous layer was then extracted withadditional dichloromethane three times. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel eluting with 5% ethyl acetate inhexanes to give 2.14 g of the title compound (7.85 mmol, 79% yield).

Example 243c2-bromo-1-(cyclopropylmethoxy)-4-(trifluoromethylsulfonyl)benzene

Example 243c was prepared according to the procedure used for thepreparation of Example 158, substituting Example 243b for Example 138a,to provide the title compound.

Example 243d4-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 243d was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 243c for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (s,1H), 8.08 (dd, J=8.85, 2.44 Hz, 1H), 7.95 (d, J=2.44 Hz, 1H), 7.50 (d,J=8.85 Hz, 1H), 7.44 (s, 1H), 7.35 (t, J=2.75 Hz, 1H), 6.12-6.13 (m,1H), 4.09 (d, J=7.02 Hz, 2H), 3.58 (s, 3H), 1.11-1.17 (m, 1H), 0.48-0.50(m, 2H), 0.29-0.33 (m, 2H). MS (ESI+) m/z 427.0 (M+H)⁺.

Example 2444-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 244a

Example 244a was prepared according to the procedure used for thepreparation of Example 96a, substituting cyclopropylmethanamine forcyclohexanamine, and Example 243b for Example 86a, respectively, toprovide the title compound.

Example 244b4-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 244b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 244a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.16 (s,1H), 7.80 (dd, J=8.85, 2.44 Hz, 1H), 7.53 (d, J=2.44 Hz, 1H), 7.29-7.31(m, 2H), 7.02 (d, J=9.16 Hz, 1H), 6.41 (t, J=5.8 Hz, 1H), 5.96-5.97 (m,1H), 3.56 (s, 3H), 3.10 (t, J=6.26 Hz, 2H), 1.01-1.06 (m, 1H), 0.39-0.43(m, 2H), 0.16-0.20 (m, 2H). MS (ESI+) m/z 426.1 (M+H)⁺.

Example 2456-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 245a5-bromo-6-(cyclopropylmethylamino)-N,N-dimethylpyridine-3-sulfonamide

Example 245a was prepared according to the procedure used for thepreparation of Example 96a, substituting cyclopropylmethanamine forcyclohexanamine, and Example 110a for Example 86a, respectively, toprovide the title compound.

Example 245b6-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 245b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 245a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.16 (s,1H), 8.35 (d, J=2.44 Hz, 1H), 7.51 (d, J=2.44 Hz, 1H), 7.20-7.32 (m,2H), 6.69 (t, J=5.34 Hz, 1H), 6.03-6.04 (m, 1H), 3.58 (s, 3H), 3.24 (t,J=5.95 Hz, 2H), 2.62 (s, 6H), 1.05-1.12 (m, 1H), 0.34-0.39 (m, 2H),0.15-0.19 (m, 2H). MS (ESI+) m/z 402.1 (M+H)⁺.

Example 2466-(2,4-difluorophenoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

The title compound was isolated as a minor product in the preparation ofExample 242b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.19 (s, 1H), 8.45 (d,J=2.44 Hz, 1H), 8.22 (d, J=2.44 Hz, 1H), 7.60 (q, J=4.78 Hz, 1H), 7.57(s, 1H), 7.46-7.52 (m, 3H), 7.36 (t, J=2.75 Hz, 1H), 7.14-7.19 (m, 1H),6.34-6.35 (m, 1H), 3.61 (s, 3H), 2.50 (d, J=4.88 Hz, 3H). MS (ESI+) m/z477.1 (M+H)⁺.

Example 2474-[2-(cyclopropylmethoxy)-6-methylphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 247a 2-bromo-1-(cyclopropylmethoxy)-3-methylbenzene

A 250 mL flask with stirbar was charged with 2-bromo-3-methylphenol(2.86 g, 15.3 mmol), (bromomethyl)cyclopropane (1.80 mL, 18.6 mmol) andcesium carbonate (7.46 g, 22.9 mmol) in dimethylformamide (50 mL). Themixture was stirred for 16 hours at ambient temperature and then heatedat 50° C. for 3 hours. The mixture was cooled to ambient temperature andpartitioned between ethyl acetate (200 mL) and saturated aqueous sodiumchloride (200 mL). The organics were washed twice with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered, andconcentrated to provide the title compound (3.7 g, 100%).

Example 247b4-(2-(cyclopropylmethoxy)-6-methylphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 247b was prepared according to the procedure used for thepreparation of Example 7d, substituting the product of Example 247a forthe product of Example 7c and stirring at 65° C. for 2.5 hours, toprovide the title compound.

Example 247c4-(2-(cyclopropylmethoxy)-6-methylphenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 247c was prepared according to the procedure used for thepreparation of Example 4b, substituting the product of Example 247b forthe product of Example 4a to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) □ ppm 11.91 (bds, 1H), 7.23-7.18 (m, 2H), 6.99 (s, 1H),6.91 (d, J=3.1 Hz, 1H), 6.89 (m, 1H), 5.79 (m, 1H), 3.74 (dd, J=6.6, 2.3Hz, 2H), 3.54 (s, 3H), 2.06 (s, 3H) 0.99 (m, 1H), 0.33 (m, 2H), 0.08 (m,2H). MS (DCI+) m/z 309.1 (M+H)⁺.

Example 2484-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 248a 2-bromo-4-(ethylsulfonyl)-1-(4-methoxycyclohexyloxy)benzene

4-Methoxycyclohexanol (a mixture of 70% cis and 30% trans isomers)(0.521 g, 4.00 mmol) in dioxane (20 mL) was treated with sodium hydride(0.240 g, 6.00 mmol). The reaction mixture was stirred for 10 minutes.To this solution was added Example 168b (0.534 g, 2 mmol). The reactionwas heated at 60° C. for 16 hours. After cooling, the reaction mixturewas partitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate two more times. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 70:30 ethylacetate/hexanes) to give the title compound (0.29 g, 38.4% yield).

Example 248b4-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 248b (second eluting peak) was prepared according to theprocedure used for the preparation of Example 95d, substituting Example248a for Example 95c, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.05 (s, 1H), 7.78-7.80 (m, 2H), 7.38-7.40 (m, 1H), 7.34(s, 1H), 7.29 (t, J=2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.63-4.66 (m, 1H),3.56 (s, 3H), 3.28 (t, J=7.32 Hz, 2H), 3.19-3.23 (m, 1H), 3.15 (s, 3H),1.65-1.72 (m, 6H), 1.42-1.48 (m, 2H), 1.13 (t, J=7.32, 3H). MS (ESI+)m/z 445.0 (M+H)⁺.

Example 2494-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamideExample 249a 3-bromo-4-(cyclopropylmethoxy)benzenesulfonamide

Example 249a was prepared according to the procedure used for thepreparation of Example 29a, substituting3-bromo-4-fluorobenzenesulfonamide for Example 2a, andcyclopropylmethanol for tetrahydro-2H-pyran-4-ol, to provide the titlecompound.

Example 249b4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

Example 249b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 249a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.03 (s,1H), 7.80 (d, J=2.44 Hz, 1H), 7.76 (dd, J=8.54, 2.44 Hz, 1H), 7.31 (s,1H), 7.30 (t, J=2.9 Hz, 1H), 7.22-7.25 (m, 3H), 6.15-6.16 (m, 1H), 3.93(d, J=6.71 Hz, 2H), 3.57 (s, 3H), 1.08-1.13 (m, 1H), 0.44-0.49 (m, 2H),0.25-0.28 (m, 2H). MS (ESI+) m/z 374.1 (M+H)⁺.

Example 2504-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

The title compound was isolated as a minor product in the preparation ofExample 249b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s, 1H), 7.70-7.74(m, 2H), 7.35 (s, 1H), 7.30 (t, J=2.9 Hz, 1H), 7.26-7.32 (m, 3H), 6.14(t, J=2.44 Hz, 1H), 3.95 (d, J=6.71 Hz, 2H), 3.58 (s, 3H), 2.41 (d,J=4.88 Hz, 3H), 1.07-1.15 (m, 1H), 0.45-0.50 (m, 2H), 0.26-0.29 (m, 2H).MS (ESI+) m/z 388.1 (M+H)⁺.

Example 251N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 251a 2-bromo-1-(cyclopropylmethoxy)-3-methyl-4-nitrobenzene

Example 251a was prepared according to the procedure used for thepreparation of Example 247a, substituting 2-bromo-3-methyl-4-nitrophenolfor 2-bromo-3-methylphenol, to provide the title compound.

Example 251b4-(6-(cyclopropylmethoxy)-2-methyl-3-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 251b was prepared according to the procedure used for thepreparation of Example 7d, substituting the product of Example 251a forthe product of Example 7c and stirring at 65° C. for 2.5 hours, toprovide the title compound.

Example 251c4-(3-amino-6-(cyclopropylmethoxy)-2-methylphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 251c was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 251b forthe product of Example 2b to provide the title compound.

Example 251dN-(4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide

Example 251 d was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 251c forExample 3, and ethanesulfonyl chloride for methanesulfonyl chloride,respectively, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) □ppm 11.93 (bds, 1H), 8.89 (bds, 1H), 7.23-7.19 (m, 2H), 6.99 (s, 1H),6.91 (d, J=3.1 Hz, 1H), 5.75 (m, 1H), 3.74 (dd, J=6.6, 2.3 Hz, 2H), 3.54(s, 3H), 3.07 (m, 2H), 2.06 (s, 3H), 1.27 (m, 3H), 0.99 (m, 1H), 0.33(m, 2H), 0.08 (m, 2H). MS (ESI+) m/z 416.1 (M+H)⁺.

Example 2524-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 252a 1-(2,4-difluorophenoxy)-4-(methylsulfonyl)-2-nitrobenzene

A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (20 g, 91 mmol),2,4-difluorophenol (11.87 g, 91 mmol) and potassium carbonate (12.6 g,91 mmol) in DMSO (90 mL) was heated at 120° C. for 2 hours. The reactionmixture was quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 1:1 ethyl acetate/hexanes) to provide the title compound (28 g, 89%yield).

Example 252b 2-(2,4-difluorophenoxy)-5-(methylsulfonyl)aniline

A solution of Example 252a (10.0 g, 30.4 mmol) in tetrahydrofuran (150mL) was added to 10% Pd/C (1.616 g, 15.18 mmol) in a 250 mL bottle andthe mixture was stirred for 24 hour under a 30 psi hydrogen atmosphereat 40° C. The mixture was filtered through a nylon membrane andconcentrated. The residue was purified flash chromatography (silica gel,70:30 ethyl acetate/hexanes) to provide the title compound (8.6 g, 55%yield).

Example 252c 1-(2,4-difluorophenoxy)-2-iodo-4-(methylsulfonyl)benzene

Example 252b (5.00 g, 16.7 mmol) in dioxane (30 mL) was treated withconcentrated HCl (150 mL) at 0° C. The reaction mixture was stirred at0° C. for 10 minutes. To this solution was added sodium nitrite (1.383g, 20.05 mmol) in water (6 mL). The reaction mixture was stirred at 0°C. for one hour. To this solution was added potassium iodide (5.55 g,33.4 mmol) in water (20 mL). The reaction mixture was stirred for twohours at 10° C. The reaction mixture was then partitioned between waterand ethyl acetate. The organic layer was extracted with additional ethylacetate twice. The combined organic layer was washed with saturatedaqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered,and concentrated. The residue was purified by flash chromatography(silica gel, 2:3 ethyl acetate/hexanes) to provide the title compound(8.9 g, 89% yield)

Example 252d ethyl1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 70e (2 g, 5.14 mmol), bis(pinacolato)diboron (2.61g, 10.3 mmol), potassium acetate (1.11 g, 11.3 mmoltris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.257 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.245 g, 0.514mmol) in dioxane (50 mL) was stirred at 90° C. for 16 hour under anargon atmosphere. The mixture was filtered through Celite, washed withethyl acetate several times and concentrated. The residue was purifiedby flash chromatography (silica gel, 50-75% ethyl acetate/petroleumether gradient) to afford the title compound (1.15 g, 40% yield).

Example 252e ethyl1-benzyl-4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 252d (2.3 g, 5.27 mmol), Example 252c (2.270 g, 5.54 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.154 g,0.527 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132mmol) and potassium phosphate (1.119 g, 5.27 mmol) were combined andsparged with argon for 30 minutes. A mixture of degassed dioxane (30 mL)and water (7.5 mL) was added and the reaction mixture was stirred at 60°C. for 16 hours. The reaction mixture was cooled to ambient temperatureand partitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried (anhydrous sodiumsulfate), filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 20-100% ethyl acetate in petroleum ether) toafford the title compound (1.77 g, 33.4% yield).

Example 252f ethyl4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 252e, anisole (1.585 mL, 14.51 mmol) andconcentrated sulfuric acid (4.3 mL, 81 mmol) in trifluoroacetic acid (20mL, 260 mmol) was heated at 90° C. for 4 hours. Excess trifluoroaceticacid was removed under reduced pressure, and the residue was partitionedbetween water (100 mL) and ethyl acetate (200 mL). The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate (2×200 mL). The combined organic layers were washed withsaturated aqueous sodium bicarbonate (100 mL), followed by saturatedaqueous sodium chloride (100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was taken intomethanol (50 mL) and the resulting solid was filtered, rinsed withmethanol, and dried to provide the title compound (3.1 g, 63% yield).

Example 252g4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

Example 252f (1.1 g, 2.2 mmol) in dioxane (60 mL) was treated with 2.0 Maqueous lithium hydroxide (4.38 mL, 8.76 mmol). The reaction mixture washeated at 65° C. for two hours. The reaction mixture was cooled toambient temperature and the solvent was removed under reduced pressure.The residue was dissolved in water (50 mL) and the pH adjusted to 5 withHCl (3M). The resulting solid was filtered and dissolved in ethylacetate (200 mL). The solution was dried over anhydrous sodium sulfate,filtered, and concentrated to provide the title compound (0.85 g, 77%yield).

Example 252h4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

To a solution of Example 252g (0.10 g, 0.21 mmol) in anhydrousdichloromethane (5 mL) was added oxalyl chloride (0.037 mL, 0.42 mmol)and dimethylformamide (0.816 μl, 10.5 μmol) The reaction mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated. The residue was redissolved in dichloromethane (5 mL) andtreated with ammonium hydroxide (2 mL, 92 mmol) and the reaction mixturewas stirred at ambient temperature for 16 hours. The reaction mixturewas partitioned between water (15 mL) and ethyl acetate (25 mL). Theaqueous layer was extracted with additional ethyl acetate (2×15 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was triturated with ethylacetate and the resulting solid was filtered, washed withdichloromethane and dried under vacuo to provide the title compound (48mg, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.33 (s, 1H), 7.98 (s,1H), 7.98-7.88 (m, 1H), 7.82 (s, 1H), 7.56-7.40 (m, 4H), 7.19 (m, 1H),7.00 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 3.59 (s, 3H), 3.27 (s, 3H). MS(ESI+) m/z 474.1 (M+H)⁺

Example 2534-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 253 was prepared according to the procedure used for thepreparation of Example 252h, substituting ethanamine for ammoniumhydroxide, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 12.32 (s, 1H), 8.35-8.32 (m, 1H), 7.98 (s, 1H), 7.89 (dd, J=2.4, 6.4Hz, 1H), 7.56-7.21 (m, 3H), 7.20-7.16 (m, 1H), 7.01 (d, J=8.4 Hz, 1H),6.85 (s, 1H), 3.59 (s, 3H), 3.30-3.23 (m, 5H), 1.11 (t, J=7.2 Hz, 3H).MS (ESI+) m/z 502.1 (M+H)⁺.

Example 2544-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 254 was prepared according to the procedure used for thepreparation of Example 252h, substituting 2,2,2-trifluoroethanamine forammonium hydroxide, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.56 (s, 1H), 8.94 (t, J=6 Hz, 1H), 7.99 (s, 1H),7.98-7.89 (m, 1H), 7.52-7.50 (m, 2H), 7.42-7.40 (m, 1H), 7.17 (m, 1H),7.03-7.00 (m, 2H), 4.13-4.08 (m, 2H), 3.59 (s, 3H), 3.26 (s, 3H). MS(ESI+) m/z 556.1 (M+H)⁺.

Example 2554-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-4-ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 255 was prepared according to the procedure used for thepreparation of Example 252h, substituting morpholine for ammoniumhydroxide, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.99 (s, 1H), 7.88 (dd, J=2.4, 6 Hz, 1H), 7.59-7.42 (m, 3H),7.22-7.17 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.50 (s, 1H), 3.59 (s, 3H),3.55 (m, 8H), 3.27 (s, 3H). MS (ESI+) m/z 544.2 (M+H)⁺.

Example 2564-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 256 was prepared according to the procedure used for thepreparation of Example 252h, substituting 1-methylpiperazine forammonium hydroxide, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.97 (d, J=2 Hz, 1H), 7.84 (dd, J=2.4, 6 Hz, 1H), 7.32(s, 1H), 7.13-7.10 (m, 2H), 6.94-6.91 (m, 2H), 6.51 (s, 1H), 3.68-3.65(m, 4H), 3.60 (s, 3H), 3.08 (s, 3H), 2.38 (m, 4H), 2.24 (s, 3H). MS(ESI+) m/z 557.2 (M+H)⁺.

Example 2574-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(1,3-thiazol-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 257 was prepared according to the procedure used for thepreparation of Example 252h, substituting thiazol-2-amine for ammoniumhydroxide, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 12.82 (s, 1H), 12.49 (s, 1H), 8.01 (s, 1H), 7.92 (dd, J=2.4, 6.4 Hz,1H), 7.56-7.45 (m, 4H), 7.34-7.29 (m, 2H), 7.22-7.18 (m, 1H), 7.03 (d,J=8.4 Hz, 1H), 3.61 (s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 557.1 (M+H)⁺.

Example 258 ethyl4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]piperidine-1-carboxylate

Example 258 was prepared according to the procedure used for thepreparation of Example 158, substituting ethyl4-hydroxypiperidine-1-carboxylate for cyclopropylmethanol, to providethe title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.01 (s, 1H),7.84-7.87 (m, 2H), 7.41 (d, J=9.46 Hz, 1H), 7.31 (s, 1H), 7.27 (t,J=2.59 Hz, 1H), 6.12 (s, 1H), 4.75-4.79 (m, 1H), 3.98 (q, J=7.02 Hz,2H), 3.56 (s, 3H), 3.22-3.26 (m, 2H), 3.20 (s, 3H), 2.10 (s, 1H),1.83-1.88 (m, 2H), 1.43-1.55 (M, 2H), 1.13 (t, J=7.02 Hz, 3H). MS (ESI+)m/z 474.1 (M+H)⁺.

Example 2594-[2-ethoxy-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The title compound was isolated as a minor product in the preparation ofExample 258. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.02 (s, 1H), 7.88 (dd,J=8.54, 2.44 Hz, 1H), 7.82 (d, J=2.44 Hz, 1H), 7.32-7.34 (m, 2H), 7.28(t, J=2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.17 (q, J=6.92 Hz, 2H), 3.57 (s,3H), 3.21 (s, 3H), 3.20 (s, 3H), 1.22 (t, J=7.02 Hz, 3H). MS (ESI+) m/z347.1 (M+H)⁺.

Example 2604-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The title compound (first eluting peak) was isolated as a second productin the preparation of Example 248b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.03 (s, 1H), 7.78-7.81 (m, 2H), 7.40 (d, J=8.54 Hz, 1H), 7.31 (s, 1H),7.28 (t, J=2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.57-4.61 (m, 1H), 3.56 (s,3H), 3.28 (t, J=7.32 Hz, 2H), 3.19 (s, 3H), 3.14-3.18 (m, 1H), 1.93-1.97(m, 2H), 1.73-1.77 (m, 2H), 1.31-1.42 (m, 4H), 1.13 (t, J=7.32, 3H). MS(ESI+) m/z 445.0 (M+H)⁺.

Example 2614-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 261a (3-bromo-4-fluorophenyl)(isopropyl)sulfane

Example 261a was prepared according to the procedure used for thepreparation of Example 168a, substituting 2-iodopropane for iodoethane,to provide the title compound.

Example 261b 2-bromo-1-fluoro-4-(isopropylsulfonyl)benzene

Example 261b was prepared according to the procedure used for thepreparation of Example 168b, substituting Example 261a for Example 168a,to provide the title compound.

Example 261c 2-bromo-N-(cyclopropylmethyl)-4-(isopropylsulfonyl)aniline

Example 261c was prepared according to the procedure used for thepreparation of Example 147a, substituting cyclopropylmethanamine forcyclohexanamine, and Example 261b for2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the titlecompound.

Example 261d4-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 261d was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 261c for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.12 (s,1H), 7.59 (dd, J=8.7, 2.29 Hz, 1H), 7.40 (d, J=2.44 Hz, 1H), 7.30 (t,J=2.9 Hz, 1H), 7.25 (s, 1H), 6.88 (d, J=8.85 Hz, 1H), 5.98-5.99 (m, 1H),5.61 (br s, 1H), 3.56 (s, 3H), 3.22-3.30 (m, 2H), 3.03 (d, J=6.71 Hz,2H), 1.16 (d, J=7.02 Hz, 6H), 0.98-1.14 (m, 1H), 0.36-0.41 (m, 2H),0.14-0.18 (m, 2H). MS (ESI+) m/z 400.1 (M+H)⁺.

Example 262N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide

Example 262 was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 251c forExample 3, to provide the title compound. ¹H NMR (500 MHz, CD₃OD) □ ppm7.34 (d, J=8.9 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H), 6.98 (s, 1H), 6.93 (d,J=8.9 Hz, 1H), 5.93 (d, J=2.8 Hz, 1H), 3.78 (m, 2H), 3.69 (s, 3H), 2.98(s, 3H), 2.13 (m, 3H), 0.99 (m, 1H), 0.35 (m, 2H), 0.08 (m, 2H). MS(ESI+) m/z 402.1 (M+H)⁺.

Example 263N-[4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamideExample 263a 1-bromo-2-(cyclopropylmethoxy)-4-methyl-5-nitrobenzene

Example 263a was prepared according to the procedure used for thepreparation of Example 247a, substituting 2-bromo-5-methyl-4-nitrophenolfor 2-bromo-3-methylphenol to provide the title compound.

Example 263b4-(2-(cyclopropylmethoxy)-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 263b was prepared according to the procedure used for thepreparation of Example 7d, substituting the product of Example 263a forthe product of Example 7c and stirring at 65° C. for 2.5 hours, toprovide the title compound.

Example 263c4-(5-amino-2-(cyclopropylmethoxy)-4-methylphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 263c was prepared according to the procedure used for thepreparation of Example 3, substituting the product of Example 263b forthe product of Example 2b to provide the title compound.

Example 263dN-(4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide

Example 263d was prepared according to the procedure used for thepreparation of Example 4 (Method A), substituting Example 263c forExample 3, to provide the title compound. ¹H NMR (500 MHz, CD₃OD) □ ppm7.36 (s, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.28 (s, 1H), 6.96 (s, 1H), 6.35(d, J=2.8 Hz, 1H), 3.84 (d, J=6.7 Hz, 2H), 3.69 (s, 3H), 3.11 (s, 3H),2.41 (s, 3H), 1.11 (m, 1H), 0.47 (m, 2H), 0.24 (m, 2H). MS (ESI+) m/z402.1 (M+H)⁺.

Example 2644-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 264a 4-(2-bromo-4-(ethylsulfonyl)phenoxy)tetrahydro-2H-thiopyran

Example 264a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168b for Example 138a,and tetrahydro-2H-thiopyran-4-ol for cyclopropylmethanol, respectively,to provide the title compound.

Example 264b4-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 264b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 264a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.79-7.82 (m, 2H), 7.40 (d, J=9.77 Hz, 1H), 7.34 (s, 1H), 7.30 (t,J=2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.69-4.72 (m, 1H), 3.58 (s, 3H), 3.28(d, J=7.32 Hz, 2H), 2.50-2.62 (m, 4H), 2.06-2.12 (m, 2H), 1.74-1.81 (m,2H), 1.13 (d, J=7.32 Hz, 6H). MS (ESI+) m/z 433.1 (M+H)⁺.

Example 2654-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 265 was prepared according to the procedure used for thepreparation of Example 168b, substituting 264b for Example 168a, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.09 (s,1H), 7.83-7.87 (m, 2H), 7.48 (d, J=8.85 Hz, 1H), 7.35 (s, 1H), 7.29 (t,J=2.75 Hz, 1H), 6.14-6.15 (m, 1H), 4.90-4.93 (m, 1H), 3.58 (s, 3H), 3.30(q, J=7.43 Hz, 2H), 3.01-3.04 (m, 2H), 2.76-2.82 (m, 2H), 2.12-2.18 (m,4H), 1.14 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 465.1 (M+H)⁺.

Example 2666-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 266a5-bromo-6-(2,4-difluorophenoxy)-N,N-dimethylpyridine-3-sulfonamide

Example 242a (0.365 g, 1 mmol) in dimethylformamide (5 mL) was treatedwith 60% sodium hydride (0.120 g, 3.00 mmol). The solution was stirredfor 10 minutes. To this solution was added iodomethane (0.355 g, 2.500mmol). The reaction mixture was stirred at ambient temperature for 2hours. The reaction mixture was partitioned between water and ethylacetate. The aqueous layer was extracted with additional ethyl acetatetwo more times. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography on silica gel to give the title compound (0.365 g, 0.928mmol, 93% yield).

Example 266b6-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 266b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 266a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.17 (s,1H), 8.50 (d, J=2.44 Hz, 1H), 8.18 (d, J=2.44 Hz, 1H), 7.57 (s, 1H),7.46-7.51 (m, 2H), 7.35 (t, J=2.75 Hz, 1H), 7.15-7.18 (m, 1H), 6.33-6.34(m, 1H), 3.61 (s, 3H), 2.71 (s, 6H). MS (ESI+) m/z 461.1 (M+H)⁺.

Example 2674-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 267a 2-bromo-N-cyclopropyl-4-(ethylsulfonyl)aniline

Example 267a was prepared according to the procedure used for thepreparation of Example 147a, substituting cyclopropylamine forcyclohexanamine, and Example 168b for2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the titlecompound.

Example 267b4-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 267b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 267a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.32 (s,1H), 7.92 (dd, J=8.7, 2.29 Hz, 1H), 7.68 (d, J=2.44 Hz, 1H), 7.51 (t,J=2.75 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J=8.54 Hz, 1H), 6.14-6.15 (m,1H), 6.11 (s, 1H), 3.77 (s, 3H), 3.40 (q, J=7.32 Hz, 2H), 2.63-2.67 (m,1H), 1.35 (t, J=7.32 Hz, 3H), 0.95-0.97 (m, 2H), 0.62-0.68 (m 2H). MS(ESI+) m/z 372.1 (M+H)⁺.

Example 2684-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-oneExample 268a8-(2-bromo-4-(ethylsulfonyl)phenoxy)-1,4-dioxaspiro[4.5]decane

Example 268a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168b for Example 138a,and 1,4-dioxaspiro[4.5]decan-8-ol for cyclopropylmethanol, respectively,to provide the title compound.

Example 268b 4-(2-bromo-4-(ethylsulfonyl)phenoxy)cyclohexanone

Example 268b was prepared according to the procedure used for thepreparation of Example 199, substituting Example 268a for Example 197,to provide the title compound.

Example 268c(cis)-4-(2-bromo-4-(ethylsulfonyl)phenoxy)-1-methylcyclohexanol

Example 268b (0.95 g, 2.63 mmol) in THF (15 mL) was cooled to 0° C. Thissolution was treated with 3.0 M methylmagnesium bromide (2.63 ml, 7.89mmol) and stirred at room temperature overnight. The reaction mixturewas quenched with saturated NH₄Cl solution and partitioned between waterand ethyl acetate. The aqueous layer was extracted with additional ethylacetate twice. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified byflash column chromatography on silica gel eluting with 1:1 ethylacetate/hexanes to give two fractions. Example 268c was the firstfraction to elute from the column.

Example 268d2-bromo-4-(ethylsulfonyl)-1-((cis)-4-methoxy-4-methylcyclohexyloxy)benzene

Example 268c (0.43 g, 1.140 mmol) in tetrahydrofuran (5 mL) was treatedwith 60% sodium hydride (0.182 g, 4.5 mmol). The reaction was stirred atambient temperature for 10 minutes. To this solution was addediodomethane (2) (0.65 g, 4.5 mmol). The reaction mixture was heated at40° C. for 16 ours. The reaction mixture was partitioned between waterand ethyl acetate. The aqueous layer was extracted with additional ethylacetate two more times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on silica gel to give the title compound (0.356 g, 0.910mmol, 80% yield).

Example 268e4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 268e was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 268d for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.04 (s,1H), 7.77-7.81 (m, 2H), 7.39 (d, J=8.85 Hz, 1H), 7.31 (s, 1H), 7.29 (t,J=2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.50-4.55 (m, 1H), 3.57 (s, 3H), 3.28(q, J=7.32 Hz, 2H), 1.69-1.78 (m, 4H), 1.46-1.53 (m, 2H), 1.33-1.38 (m,2H), 1.13 (t, J=7.32 Hz, 3H), 1.05 (s, 3H). MS (ESI+) m/z 459.1 (M+H)⁺.

Example 2694-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N,N,6-trimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 269 was prepared according to the procedure used for thepreparation of Example 252h, substituting dimethylamine for ammoniumhydroxide, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.08 (s, 1H), 7.95 (dd, J=2.4, 6 Hz, 1H), 7.43 (s, 1H), 7.26-7.15(m, 2H), 7.05-6.99 (m, 2H), 6.69 (s, 1H), 3.72 (s, 3H), 3.25 (s, 3H),3.19 (s, 3H), 3.12 (s, 1H). MS (ESI+) m/z 502.0 (M+H)⁺.

Example 2706-methyl-4-{5-(methylsulfonyl)-2-[4-(methylsulfonyl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 270 was prepared according to the procedure used for thepreparation of Example 138b, substituting 4-(methylsulfonyl)phenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.08 (s, 1H), 8.06 (d, J=2.44 Hz, 1H), 7.97 (dd, J=8.7,2.29 Hz, 1H), 7.85-7.88 (m, 2H), 7.40 (s, 1H), 7.35 (d, J=8.54 Hz, 1H),7.29 (t, J=2.75 Hz, 1H), 7.20-7.23 (m, 2H), 6.24-6.25 (m, 1H), 3.54 (s,3H), 3.30 (s, 3H), 3.17 (s, 3H). MS (ESI+) m/z 471.2 (M+H)⁺.

Example 2714-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 271a2-bromo-1-(2,4-difluorophenoxy)-4-(isopropylsulfonyl)benzene

Example 271a was prepared according to the procedure used for thepreparation of Example 138b, substituting Example 261b for Example 138a,to provide the title compound.

Example 271b4-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 271b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 271a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.11 (s,1H), 7.88 (d, J=2.44 Hz, 1H), 7.80 (dd, J=8.85, 2.44 Hz, 1H), 7.50-7.54(m, 1H), 7.42-7.49 (m, 2H), 7.31 (t, J=2.75 Hz, 1H), 7.15-7.19 (m, 1H),7.00 (d, J=8.54, Hz, 1H), 6.25-6.26 (m, 1H), 3.59 (s, 3H), 3.44-3.48 (m,1H), 1.20 (d, J=7.02 Hz, 6H). MS (ESI+) m/z 459.0 (M+H)⁺.

Example 2726-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamideExample 272a5-bromo-6-(cyclopropylmethoxy)-N,N-diethylpyridine-3-sulfonamide

Example 272a was prepared according to the procedure used for thepreparation of Example 266a, substituting Example 207a for Example 242a,and ethyl iodide for iodomethane, respectively, to provide the titlecompound.

Example 272b6-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 272b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 272a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (s,1H), 8.54 (d, J=2.44 Hz, 1H), 8.01 (d, J=2.44 Hz, 1H), 7.44 (s, 1H),7.32 (t, J=2.75 Hz, 1H), 6.15-6.16 (m, 1H), 4.24 (d, J=7.02 Hz, 2H),3.58 (s, 3H), 3.21 (q, J=7.02 Hz, 4H), 1.17-1.20 (m, 4H), 1.08 (t,J=7.02 Hz, 6H), 0.47-0.51 (m, 2H), 0.29-0.32 (m, 2H). MS (ESI+) m/z431.1 (M+H)⁺.

Example 2734-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamideExample 273a3-bromo-4-(cyclopropylmethoxy)-N,N-dimethylbenzenesulfonamide

Example 273a was prepared according to the procedure used for thepreparation of Example 266a, substituting Example 249a for Example 242a,to provide the title compound.

Example 273b4-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

Example 273b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 273a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.70 (dd, J=8.54, 2.44 Hz, 1H), 7.66 (d, J=2.44 Hz, 1H), 7.37 (s,1H), 7.29-7.32 (m, 2H), 6.12-6.13 (m, 1H), 3.98 (d, J=6.71 Hz, 2H), 3.57(s, 3H), 2.62 (s, 6H), 3.21 (q, J=7.02 Hz, 4H), 1.11-1.15 (m, 1H),0.46-0.49 (m, 2H), 0.27-0.30 (m, 2H). MS (ESI+) m/z 402.1 (M+H)⁺.

Example 2744-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 274a 2-bromo-1-(cyclopropylmethoxy)-4-fluorobenzene

To a solution of 2-bromo-4-fluorophenol (0.50 g, 2.6 mmol) intetrahydrofuran (13 mL) were added cyclopropanemethanol (0.209 mL, 2.62mmol), triphenylphosphine (0.687 g, 2.62 mmol), and DIAD (0.509 mL, 2.62mmol). The reaction mixture was stirred for 16 hours at ambienttemperature. The solvent was removed under reduced pressure. The residuewas triturated with hexanes. The mixture was filtered, and the filtratecontaining the product was concentrated by under reduced pressure. Theresidue was purified by flash chromatography (silica gel, hexanes) toprovide the title compound (400 mg, 62% yield).

Example 274b (2-(cyclopropylmethoxy)-5-fluorophenyl)boronic acid

To a solution of Example 274a (0.1 g, 0.408 mmol) in tetrahydrofuran (2mL) at −20° C. was added nBuLi (0.180 mL of a 2.5 M solution in hexanes,0.449 mmol). The reaction mixture was stirred for 2 hours, then cooledto −40° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.092mL, 0.449 mmol) was added dropwise. The reaction mixture was stirred for30 minutes. The reaction mixture was quenched with 1M citric acid at 0°C. The mixture was stirred at ambient temperature for 1 hour and thenextracted with ethyl acetate. The layers were separated, and the organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was purified by flash chromatography(silica gel, 10-33% ethyl acetate/hexanes gradient) to provide the titlecompound (23 mg, 20% yield).

Example 274c4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Nitrogen was bubbled through a 4:1 dimethoxyethane/ethanol solution for20 minutes. A microwave vial was charged with Example 1e (0.05 g, 0.131mmol), Example 274b (0.046 g, 0.144 mmol), Pd(Ph₃P)₄ (7.58 mg, 6.56μmol), and cesium fluoride (0.060 g, 0.393 mmol). The vial was sealedand flushed with nitrogen. The 4:1 dimethoxyethane/ethanol mixture (0.5mL) was added. The reaction mixture was heated in a microwave reactor at120° C. for 40 minutes. The reaction mixture was partitioned betweenwater and ethyl acetate. The layers were separated. The aqueous layerwas extracted with ethyl acetate. The combined organics were dried overanhydrous sodium sulfate, filtered, and concentrated. The crude materialwas purified by flash chromatography (silica gel, 20-80% ethylacetate/hexanes gradient) to provide the title compound (5 mg, 23%yield). ¹H NMR (300 MHz, DMSO-d₆) □ ppm 11.98 (s, 1H), 7.29 (s, 1H),7.26 (t, J=2.71 Hz, 1H), 7.05-7.18 (m, 3H), 6.14 (dd, J=2.71, 2.03 Hz,1H), 3.80 (d, J=6.78 Hz, 2H), 3.55 (s, 3H), 0.98-1.09 (m, 1H), 0.39-0.46(m, 2H), 0.17-0.22 (m, 2H). MS (ESI+) m/z 313.1 (M+H)⁺.

Example 2754-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 275a 2-bromo-1-(2,4-difluorophenoxy)-4-(trifluoromethyl)benzene

A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52 mmol),2,4-difluorophenol (0.337 mL, 3.52 mmol), and potassium carbonate (0.486g, 3.52 mmol) in dimethylformamide (7 mL) was heated at 80° C. for 16hours. The reaction mixture was cooled to ambient temperature andpartitioned between ethyl acetate and water. The layers were separated,and the aqueous layer was extracted with ethyl acetate. The combinedorganics were washed with water and saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude material was purified by flash chromatography (silica gel, 0-10%ethyl acetate/hexanes gradient) to provide the title compound (1.0 g,80% yield).

Example 275b (2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl)boronicacid

To a suspension of magnesium (0.083 g, 3.42 mmol) in tetrahydrofuran(1.00 mL) was added 0.5 mL of a solution of Example 275a (1.099 g, 3.11mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was warmed(about 40-50° C.) until reaction commenced. The remaining solution ofstarting bromide was added dropwise. The reaction mixture was stirred atambient temperature for 1 hour. The resulting solution was addeddropwise to a solution of trimethyl borate (0.696 mL, 6.23 mmol) intetrahydrofuran (1.5 mL) at 0° C. The reaction mixture was stirred atambient temperature for 1 hour, quenched with ice water and thenneutralized with 2 M HCl. The mixture was extracted with ethyl acetate.The combined organics were washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 10-33% ethyl acetate/hexanes gradient) to provide the titlecompound (650 mg, 66% yield).

Example 275c4-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 275c was prepared according to the procedure used for thepreparation of Example 274c, substituting example 275b for example 274b,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 12.06 (s,1H), 7.78 (d, J=2.37 Hz, 1H), 7.70 (dd, J=8.48, 1.70 Hz, 1H), 7.49 (td,J=11.36, 8.65, 3.05 Hz, 1H), 7.40 (s, 1H), 7.34-7.43 (m, 1H), 7.28 (t,J=2.71 Hz, 1H), 7.10-7.17 (m, 1H), 6.95 (d, J=8.48 Hz, 1H), 6.24 (dd,J=2.71, 2.03 Hz, 1H), 3.57 (s, 3H). MS (ESI+) m/z 421.1 (M+H)⁺.

Example 2764-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of Example 252f (0.20 g, 0.40 mmol) in tetrahydrofuran(5 mL) stirring at 0° C. was added lithium aluminum hydride (1M intetrahydrofuran, 0.398 mL, 0.398 mmol) and the mixture was stirred at 0°C. for two hours. The solvent was evaporated under reduced pressure andthe residue was partitioned between ethyl acetate (30 mL) and water (20mL). The mixture was filtered to remove the undissolved materials. Theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was triturated with dichloromethane and theresulting solid was filtered and dried to provide the title compound(0.10 g, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.91 (s, 1H), 7.97(d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.38 (m, 3H),7.20-7.15 (m, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.18 (s, 1H), 5.11 (t, J=5.6Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 3.57 (s, 3H), 3.16 (s, 3H). MS (ESI+)m/z 461.2 (M+H)⁺.

Example 2774-[2-(2,3-dihydro-1H-inden-2-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 277 was prepared according to the procedure used for thepreparation of Example 158, substituting 2,3-dihydro-1H-inden-2-ol forcyclopropylmethanol, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.97 (s, 1H), 7.91 (dd, J=8.54, 2.44 Hz, 1H), 7.85 (d,J=2.44 Hz, 1H), 7.47 (d, J=8.85 Hz, 1H), 7.20-7.23 (m, 2H), 7.12-7.17(m, 3H), 7.07 (s, 1H), 6.00-6.01 (m, 1H), 5.41-5.44 (m, 1H), 3.36-3.42(m, 2H), 3.56 (s, 3H), 3.23 (s, 3H), 3.20 (s, 3H), 2.97 (dd, J=16.94,1.98 Hz, 2H). MS (ESI+) m/z 435.1 (M+H)⁺.

Example 2784-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 278a4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

To the solution of Example 276 (1.0 g, 2.2 mmol) in dichloromethane (50mL) at 0° C. was added Dess-MartinPeriodinane (1.84 g, 4.34 mmol) andthe reaction mixture was stirred at 0° C. for 30 minutes. The reactionmixture was then stirred at ambient temperature for three hours. Asolution of sodium bisulfite (0.9 g, 9 mmol) in saturated aqueous sodiumbicarbonate (5 mL) was added, and the reaction mixture was stirred for15 minutes and extracted with ethyl acetate. The organic layer was dried(anhydrous sodium sulfate), filtered, and concentrated to provide thetitle compound (0.80 g, 70% yield).

Example 278b4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a solution of Example 278a (0.20 g, 0.44 mmol) in tetrahydrofuran (6mL) at 0° C. was added methylmagnesium bromide (1.0 M intetrahydrofuran, 0.873 mL, 0.873 mmol). The reaction mixture was stirredat 0° C. for one hour, and then 1M aqueous HCl (2 mL) was added. Thereaction mixture was concentrated and partitioned between saturatedaqueous sodium chloride (10 mL) and ethyl acetate (2×30 mL). Thecombined organic phase was washed with saturated aqueous sodium chloride(30 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by preparative thin layerchromatography (silica gel, dichloromethane/methanol, 15/1) to providethe title compound (51 mg, 24% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.83 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H),7.55-7.50 (m, 1H), 7.42-7.36 (m, 2H), 7.20-7.15 (m, 1H), 6.97 (d, J=8.8Hz, 1H), 6.15 (d, J=2 Hz, 1H), 5.13 (d, J=5.2 Hz, 1H), 4.80-4.77 (m,1H), 3.57 (s, 3H), 3.25 (s, 3H), 1.38 (d, J=6.4 Hz, 3H). MS (ESI+) m/z475.1 (M+1)⁺.

Example 2794-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-[(dimethylamino)methyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a solution of Example 278a (0.20 g, 0.44 mmol) and dimethylaminehydrochloride (0.071 g, 0.873 mmol) in methanol (6 mL) was added zincchloride (0.059 g, 0.436 mmol) at ambient temperature. The reactionmixture was stirred at ambient temperature for one hour, and then sodiumcyanoborohydride (0.055 g, 0.873 mmol) was added and the reactionmixture was stirred at ambient temperature for three days. The resultingsolid was filtered and washed with methanol (10 mL), and the eluant wasconcentrated. The residue was purified by preparative thin layerchromatography (silica gel, dichloromethane/methanol, 15/1) to providethe title compound (75 mg, 34% yield). ¹H NMR (400 MHz, CD₃OD) δ ppm8.07 (d, J=2.4 Hz, 1H), 7.94 (dd, J=2.4, 6.4 Hz, 1H), 7.38 (s, 1H),7.25-7.06 (m, 2H), 7.04-6.98 (m, 2H), 6.31 (s, 1H), 3.71 (s, 3H), 3.67(s, 2H), 3.19 (s, 3H), 2.28 (s, 6H). MS (ESI+) m/z 488.1 (M+H)⁺.

Example 2804-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-4-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 280 was prepared according to the procedure used for thepreparation of Example 279, substituting morpholine for dimethylaminehydrochloride, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 11.98 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 6.4 Hz,1H), 7.56-7.50 (m, 1H), 7.44-7.38 (m, 2H), 7.19-7.16 (m, 1H), 6.99 (d,J=8.4 Hz, 1H), 6.15 (s, 1H), 3.58 (s, 3H), 3.55 (s, 2H), 3.49-3.47 (m,4H), 3.26 (s, 3H), 2.31 (m, 4H). MS (ESI+) m/z 530.2 (M+H)⁺.

Example 2814-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methylpiperazin-1-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 281 was prepared according to the procedure used for thepreparation of Example 279, substituting 1-methylpiperazine fordimethylamine hydrochloride, to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.94 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd,J=2.4, 6.4 Hz, 1H), 7.55-7.49 (m, 1H), 7.43-7.37 (m, 2H), 7.18-7.13 (m,1H), 6.99 (d, J=8.4 Hz, 1H), 6.12 (s, 1H), 3.57 (s, 3H), 3.52 (s, 2H),3.26 (s, 3H), 2.32-2.21 (m, 8H), 2.09 (s, 3H). MS (ESI+) m/z 543.2(M+H)⁺.

Example 2824-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(phenylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 282 was prepared according to the procedure used for thepreparation of Example 279, substituting aniline for dimethylaminehydrochloride, to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 11.95 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.84 (dd, J=2.4, 6.8 Hz,1H), 7.48 (m, 1H), 7.40 (s, 1H), 7.29-7.28 (m, 1H), 7.12 (m, 1H),6.99-6.91 (m, 3H), 6.58 (d, J=7.6 Hz, 2H), 6.49 (t, J=7.2 Hz, 1H), 6.19(d, J=2.0 Hz, 1H), 5.94 (m, 1H), 4.31 (d, J=6.4 Hz, 2H), 3.56 (s, 3H),3.23 (s, 3H). MS (ESI+) m/z 536.2 (M+H)⁺.

Example 2834-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(1,3-thiazol-2-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 283 was prepared according to the procedure used for thepreparation of Example 279, substituting thiazol-2-amine fordimethylamine hydrochloride, to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.99 (s, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.86-7.83 (m,2H), 7.51-7.45 (m, 1H), 7.42 (s, 1H), 7.30-7.26 (m, 1H), 7.14-7.13 (m,1H), 6.99-6.92 (m, 2H), 6.62 (d, J=3.6 Hz, 1H), 6.18 (s, 1H), 5.94 (m,1H), 4.49 (d, J=5.6 Hz, 2H), 3.58 (s, 3H), 3.24 (s, 3H). MS (ESI+) m/z543.2 (M+H)⁺.

Example 2844-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(tetrahydrofuran-3-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 284 was prepared according to the procedure used for thepreparation of Example 279, substituting tetrahydrofuran-3-amine fordimethylamine hydrochloride, to provide the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.86 (s, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.87-7.85 (m,2H), 7.54-7.39 (m, 3H), 7.18-7.16 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.17(s, 1H), 3.72-3.66 (m, 3H), 3.57-3.53 (m, 5H), 3.25 (s, 3H), 3.14-3.13(m, 1H), 2.27-2.26 (m, 1H), 1.82-1.77 (m, 1H), 1.58-1.57 (m, 1H). MS(ESI+) m/z 530.2 (M+H)⁺.

Example 2854-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 285a 1-(cyclopropylmethoxy)-4-(phenylsulfonyl)benzene

Example 285a was prepared according to the procedure used for thepreparation of Example 158, substituting1-fluoro-4-(phenylsulfonyl)benzene for Example 138a, to provide thetitle compound.

Example 285b 2-bromo-1-(cyclopropylmethoxy)-4-(phenylsulfonyl)benzene

Example 285a (0.087 g, 0.3 mmol) in acetic acid (5 mL) was cooled to 0°C. To this solution was added 1-bromopyrrolidine-2,5-dione (2) (0.059 g,0.330 mmol). The reaction mixture was heated at 80° C. for 16 hours.After cooling, the reaction mixture was partitioned between water andethyl acetate. The aqueous layer was extracted with additional ethylacetate two more times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on silica gel to give the title compound (0.032 g, 0.087mmol, 29% yield).

Example 285c4-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 285c was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 285b for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.80 (s,1H), 7.63-7.74 (m, 4H), 7.36-7.46 (m, 3H), 7.12 (s, 1H), 7.04-7.06 (m,2H), 5.80-5.81 (m, 1H), 3.72 (d, J=6.71 Hz, 2H), 3.34 (s, 3H), 0.82-0.89(m, 1H), 0.29-0.24 (m, 2H), 0.00-0.04 (m, 2H). MS (ESI+) m/z 434.9(M−H)⁺.

Example 2864-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 286a 4-(3-bromo-4-fluorophenylsulfonyl)morpholine

3-Bromo-4-fluorobenzene-1-sulfonyl chloride (0.44 g, 1.609 mmol) intetrahydrofuran (10 mL) was treated with morpholine (0.294 g, 3.38mmol). The reaction mixture was stirred for 16 hours at ambienttemperature. The solvent was removed, and the residue was loaded onto asilica gel column and eluted with 20% ethyl acetate in hexanes to givethe title compound (0.45 g, 1.388 mmol, 86% yield).

Example 286b 4-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl)morpholine

Example 286b was prepared according to the procedure used for thepreparation of Example 158, substituting Example 286a for Example 138a,to provide the title compound.

Example 286c4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 286c was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 286b for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.03 (s,1H), 7.69 (dd, J=8.85, 2.44 Hz, 1H), 7.64 (d, J=2.44 Hz, 1H), 7.37 (s,1H), 7.33 (d, J=8.85 Hz, 1H), 7.29 (t, J=2.75 Hz, 1H), 6.11-6.13 (m,1H), 3.97 (d, J=6.71 Hz, 2H), 3.62-3.65 (m, 4H), 3.57 (s, 3H), 2.86-2.88(m, 4H), 0.45-0.48 (m, 2H), 0.27-0.29 (m, 2H). MS (ESI+) m/z 444.1(M+H)⁺.

Example 2874-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 287a 3-bromo-4-(2,4-difluorophenoxy)benzaldehyde

A mixture of 3-bromo-4-fluorobenzaldehyde (4.06 g, 20 mmol),2,4-difluorophenol (2.60 g, 20 mmol) and cesium carbonate (7.17 g, 22mmol) in dimethyl sulfoxide (20 mL) was heated at 100° C. for 1 hour.The reaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride twice,dried with anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 20% ethylacetate in heptanes) to provide the title compound (5.94 g, 95%).

Example 287b (3-bromo-4-(2,4-difluorophenoxy)phenyl)methanol

To a solution of Example 287a (3.76 g, 12 mmol) in the mixture ofethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride(0.136 g, 3.60 mmol). The reaction mixture was stirred at ambienttemperature for 1 hour. The solvent was evaporated and the residue waspartitioned with ethyl acetate and water. The organic layer was washedwith saturated aqueous sodium chloride, dried with anhydrous sodiumsulfate, filtered, and concentrated to provide the title compound (3.72g, 98%).

Example 287c 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene

To a solution of Example 287b (3.70 g, 11.74 mmol) in dichloromethane(20 mL) was added phosphorus tribromide (1.11 mL, 11.7 mmol) dropwise.The reaction mixture was stirred at ambient temperature for 3 hours, andpoured into ice water. The pH was adjusted to basic by the carefuladdition of saturated aqueous sodium bicarbonate and the mixture wasextracted with dichloromethane. The organic layer was washed withsaturated aqueous sodium chloride, dried with anhydrous sodium sulfate,filtered, and concentrated to provide the title compound (4.15 g, 93%).

Example 287d (3-bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane

A mixture of Example 287c (1.512 g, 4.00 mmol) and sodium thiomethoxide(0.280 g, 4.00 mmol) in dimethylformamide (8 mL) was stirred at ambienttemperature for 6 hours. The reaction mixture was partitioned with ethylacetate and water. The organic layer was washed with saturated aqueoussodium chloride twice, dried with anhydrous sodium sulfate, filtered,and concentrated to provide the title compound (1.38 g, 100%).

Example 287e2-bromo-1-(2,4-difluorophenoxy)-4-(methylsulfonylmethyl)benzene

To a solution of Example 287d (1.38 g, 4.00 mmol) in methanol (15 mL)was added oxone (5.16 g, 8.40 mmol) in water (15 mL) at 0° C. Thereaction mixture was stirred at ambient temperature for 1 hour. Thereaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedwith anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by flash chromatography (silica gel, 20 to 40% ethylacetate in heptanes) to provide the title compound (1.49 g, 98%).

Example 287f4-(2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 287e (94 mg, 0.25 mmol), Example 6a (107 mg, 0.250 mmol),potassium phosphate (186 mg, 0.875 mmol),tris(dibenzylideneacetone)dipalladium (6.9 mg, 7.5 μmol) and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (6.6 mg,0.023 mmol) were combined in a microwave tube and purged with nitrogenfor 15 minutes. A mixture of dioxane (2 mL) and water (0.5 mL) waspurged with nitrogen for 15 minutes and transferred to the microwavetube. The reaction mixture was heated at 60° C. for 1 hour. The reactionmixture was partitioned with ethyl acetate and water. The organic layerwas washed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, treated with 3-mercaptopropyl functionalized silica gel,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 1 to 2% methanol in dichloromethane) toprovide the title compound (62 mg, 41%).

Example 287g4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 287f (59.9 mg, 0.100 mmol), potassium hydroxide (84 mg, 1.5mmol) and cetyltrimethylammonium bromide (1.8 mg, 5.0 μmol) werecombined in a mixture of tetrahydrofuran (4 mL) and water (2 mL). Thereaction mixture was heated at 100° C. for 44 hours and then cooled toambient temperature. To this mixture was added water, and the pH wasadjusted to pH 7 by the addition of 1M HCl. The mixture was extractedwith ethyl acetate and the organic layer was washed with saturatedaqueous sodium chloride twice, dried with anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 2 to 4% methanol in dichloromethane) toprovide the title compound (31 mg, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm12.04 (s, 1H) 7.57 (d, J=2.37 Hz, 1H) 7.26-7.48 (m, 4H) 7.16-7.26 (m,1H) 7.00-7.11 (m, 1H) 6.88 (d, J=8.48 Hz, 1H) 6.23-6.33 (m, 1H) 4.51 (s,2H) 3.55 (s, 3H) 2.94 (s, 3H). MS (ESI+) m/z 445 (M+H)⁺.

Example 2884-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 288a 2-fluoro-5-(methylthio)pyridine

A mixture of 5-bromo-2-fluoropyridine (2.05 g, 11.7 mmol) andN¹,N¹,N²,N²-tetramethylethane-1,2-diamine (2.27 mL, 15.1 mmol) waspurged with nitrogen for 45 minutes. Toluene (116 mL) was added and thereaction mixture was cooled to −78° C. N-butyllithium (2.5 M in hexanes,5.59 mL, 14.0 mmol) was added dropwise over 6 minutes. The reactionmixture was stirred at −78° C. for 1 hour. Dimethyl disulfide (1.26 mL,14.0 mmol) was added. The reaction mixture was stirred at −78° C. for 1hour. The reaction mixture was warmed to 0° C., then immediatelyquenched with saturated aqueous ammonium chloride. The layers wereseparated, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (10%ethyl acetate/heptane) to provide the title compound (1.00 g, 60%).

Example 288b 2-fluoro-5-(methylsulfonyl)pyridine

To a solution of Example 288a (2.17 g, 15.2 mmol) in dichloromethane(50.5 mL) was added 3-chlorobenzoperoxoic acid (7.15 g, 31.1 mmol)portionwise over 10 minutes. The reaction mixture was stirred at ambienttemperature for 4 hours. Additional 3-chlorobenzoperoxoic acid (2.62 g,15.16 mmol) was added and the reaction mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was quenched with saturatedaqueous sodium carbonate, and the layers were separated. The aqueouslayer was extracted with dichloromethane. The combined organic layerswere washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 0-10% methanol/dichloromethane) toprovide the title compound (1.81 g, 68%).

Example 288c 5-(methylsulfonyl)pyridin-2(1H)-one

Example 288b (0.679 g, 3.88 mmol) was treated with acetic acid (35.2 mL)and water (3.52 mL) at 110° C. for 16 hours. The reaction mixture wascooled to ambient temperature and the solvent was removed to provide thetitle compound (0.700 g, 100%).

Example 288d 3-bromo-5-(methylsulfonyl)pyridin-2(1H)-one

To a solution of Example 288c (0.671 g, 3.87 mmol) and sodium acetate(0.318 g, 3.87 mmol) in acetic acid (8.50 mL) was added bromine (0.201mL, 3.91 mmol) dropwise as a solution in acetic acid (1.7 mL). Thereaction mixture was stirred at 40° C. for 3 hours. Bromine (0.05 mL)was added, and the reaction mixture was stirred at 40° C. for 2 hours.The reaction mixture was cooled to ambient temperature and quenched with100 mL of 10% aqueous sodium thiosulfate. The resulting suspension wasfiltered, and the solid collected and dried for 16 hours to provide thetitle compound (0.64 g, 66%).

Example 288e 3-bromo-2-chloro-5-(methylsulfonyl)pyridine

Example 288d (0.6395 g, 2.54 mmol) was treated with phosphorusoxychloride (12.7 mL) at 110° C. for 4 hours. The reaction mixture wascooled to ambient temperature and poured onto ice. The resultingsuspension was filtered and rinsed with water, and the off white solidwas collected and dried in a 60° C. vacuum oven for 16 hours to providethe title compound (0.244 g, 35%).

Example 288f 3-bromo-2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridine

Example 288f was prepared according to the procedure used for thepreparation of Example 2b, substituting 2,4-difluorophenol for phenol,and Example 288e for Example 2a, respectively, to provide the titlecompound.

Example 288g4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 288g was prepared according to the procedure used for thepreparation of Example 4a, substituting Example 288f for Example 7c toprovide the title compound.

Example 288h4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 288h was prepared according to the procedure used for thepreparation of Example 4b, substituting Example 288g for Example 4a toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 12.16 (s,1H) 8.59 (d, J=2.37 Hz, 1H) 8.37 (d, J=2.37 Hz, 1H) 7.58 (s, 1H) 7.48(m, 2H) 7.34 (t, J=2.71 Hz, 1H) 7.16 (m, 1H) 6.36 (dd, J=2.71, 2.03 Hz,1H) 3.61 (s, 3H) 3.35 (s, 3H). MS (ESI+) m/z 432.4 (M+H)⁺.

Example 2894-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin-3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 289a2-(chloromethyl)-4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 276 (0.50 g, 1.09 mmol) and thionyl chloride (5.0mL, 69 mmol) was heated under reflux for 2 hours. The solvent wasremoved under reduced pressure and the residue was dried under vacuo for1 hour to provide the title compound.

Example 289b4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin-3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a solution of pyridin-3-ol (0.039 g, 0.407 mmol) in tetrahydrofuran(5 mL) was added sodium hydride (16 mg, 0.407 mmol) at 0° C., and themixture was stirred for 30 minutes. To this solution was added Example289a (0.25 g, o.204 mmol) and the reaction mixture was heated underreflux for 16 hours. The reaction mixture was poured into a mixture ofethyl acetate (30 mL) and saturated aqueous sodium chloride (20 mL). Theaqueous layer was extracted with ethyl acetate (20 mL). The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated. The residue was purified by reverse phase HPLC (C18,water (10 mM NH₄HCO₃):acetonitrile, 25-50% gradient) to provide thetitle compound (18 mg, 16% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.52(s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.38(m, 5H), 7.22-7.18 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.84-6.82 (m, 1H),6.48 (s, 1H), 5.38 (s, 2H), 3.58 (s, 3H), 3.25 (s, 3H). ). MS (ESI+) m/z538.1 (M+1)⁺.

Example 2904-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 290a (3-bromo-4-fluorophenyl)(cyclopropyl)sulfane

Example 290a was prepared according to the procedure used for thepreparation of Example 168a, substituting bromocyclopropane foriodoethane, to provide the title compound

Example 290b 2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene

Example 290b was prepared according to the procedure used for thepreparation of Example 168b, substituting Example 290a for Example 168a,to provide the title compound.

Example 290c2-bromo-4-(cyclopropylsulfonyl)-1-(2,4-difluorophenoxy)benzene

Example 290c was prepared according to the procedure used for thepreparation of Example 138b, substituting Example 290b for Example 138a,to provide the title compound.

Example 290d4-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 290d was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 290c for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.11 (s,1H), 7.94 (d, J=2.44 Hz, 1H), 7.83 (dd, J=8.54, 2.44 Hz, 1H), 7.42-7.55(m, 3H), 7.32 (t, J=2.75 Hz, 1H), 7.15-7.20 (m, 1H), 6.97 (d, J=8.54 Hz,1H), 6.28-6.29 (m, 1H), 3.59 (s, 3H), 2.90-2.96 (m, 1H), 1.12-1.15 (m,2H), 1.03-1.09 (m, 2H). MS (ESI+) m/z 457.1 (M+H)⁺.

Example 2914-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(prop-1-en-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a solution of Example 252f (0.10 g, 0.20 mmol) in tetrahydrofuran (6mL) stirring at 0° C. was added methylmagnesium bromide (0.498 mL, 0.498mmol). The reaction mixture was stirred at 0° C. for 1 hour, and thenaqueous HCl (1 M, 2 mL) was added. The reaction mixture was concentratedand partitioned between saturated aqueous sodium chloride (10 mL) andethyl acetate. The organic phase was washed with saturated aqueoussodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered,and concentrated. The residue was purified by reverse phase-HPLC (C 1840-90% gradient acetonitrile:water (0.1% TFA)) to provide the titlecompound (25 mg, 25% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.05 (s,1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.61-7.36 (m,3H), 7.18 (t, J=8.6 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.34 (d, J=2.2 Hz,1H), 5.85 (s, 1H), 5.07 (s, 1H), 3.60 (s, 3H), 3.26 (s, 3H), 2.02 (s,3H). MS (ESI+) m/z 471.1 (M+1)⁺.

Example 2924-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(phenoxymethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 292 was prepared according to the procedure used for thepreparation of Example 289b, substituting phenol for pyridin-3-ol, toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.32 (s,1H), 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.55-7.50 (m,1H), 7.49 (s, 1H), 7.45-7.36 (m, 1H), 7.26-7.16 (m, 3H), 6.98-6.89 (m,4H), 6.37 (s, 1H), 5.11 (s, 2H), 3.59 (s, 3H), 3.23 (s, 3H). MS (ESI+)m/z 537.2 (M+1)⁺

Example 2934-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 293a4-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)morpholine

Example 293a was prepared according to the procedure used for thepreparation of Example 138b, substituting Example 286a for Example 138a,to provide the title compound.

Example 293b4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 293b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 293a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (s,1H), 7.76 (d, J=2.44 Hz, 1H), 7.83 (dd, J=8.7, 2.44 Hz, 1H), 7.42-7.54(m, 3H), 7.30 (t, J=2.75 Hz, 1H), 7.14-7.16 (m, 1H), 7.01 (d, J=8.54 Hz,1H), 6.25-6.27 (m, 1H), 3.64-3.66 (m, 4H), 3.59 (s, 3H), 2.88-2.92 (m,4H). MS (ESI+) m/z 502.2 (M+H)⁺.

Example 2944-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 294a 3-bromo-2-chloro-5-(ethylsulfonyl)pyridine

Sodium sulfite (1.755 g, 13.92 mmol) and sodium bicarbonate (1.231 g,14.65 mmol) were dissolved in water (37 mL) to give a colorlesssolution. The mixture was heated at 75° C.3-Bromo-2-chloropyridine-5-sulfonyl chloride (2.132 g, 7.33 mmol) wasadded portionwise over 1 hour. The reaction mixture was stirred at 75°C. for 1 hour. The mixture was concentrated and N,N-dimethylformamide(13.88 mL) was added. Sodium bicarbonate (1.231 g, 14.65 mmol) andiodoethane (0.589 mL, 7.33 mmol) were added. The resulting mixture washeated to 75° C. for 2 hours and then cooled to ambient temperature. Themixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 0-100% ethylacetate/heptane) to provide the title compound.

Example 294b4-(2-chloro-5-(ethylsulfonyl)pyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 294b was prepared according to the procedure used for thepreparation of Example 4a, substituting Example 294a for Example 7c toprovide the title compound.

Example 294c4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 294c was prepared according to the procedure used for thepreparation of Example 2b, substituting 2,4-difluorophenol for phenol,and Example 294b for Example 2a, respectively, to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.17 (bs, 1H), 8.56 (d, J=2.4Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.58 (s, 1H), 7.54-7.43 (m, 2H), 7.34(t, J=2.7 Hz, 1H), 7.21-7.12 (m, 1H), 6.35 (t, J=2.1 Hz, 1H), 3.61 (s,3H), 3.44 (q, J=7.3 Hz, 2H), 1.18 (t, J=7.3 Hz, 1H). MS (ESI+) m/z 446.2(M+H)⁺.

Example 295N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamideExample 295a4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 295a was prepared according to the procedure used for thepreparation of Example 138a, substituting Example 1e for2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for Example6a, respectively, to provide the title compound.

Example 295bN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamide

A mixture of Example 295a, 2-chloroethanesulfonyl chloride (0.098 g,0.600 mmol), and triethylamine (0.081 g, 0.800 mmol) in dichloromethane(3 mL) was stirred at ambient temperature for 2 hours. The solvent wasremoved, and the residue was redissolved in MeOH (5 mL). To thissolution was added morpholine (0.697 g, 8.00 mmol). The reaction mixturewas heated at 50° C. for 2 hours. To this solution was added 2.0 Nsodium hydroxide (2.00 mL, 4.00 mmol). The reaction mixture was heatedat 85° C. for 2 hours. After cooling, the reaction mixture waspartitioned between ethyl acetate and 1.0 N HCl. The aqueous layer wasextracted with additional ethyl acetate several times. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by preparative HPLC (10-80% acetonitrile in 0.1%TFA water) to give the TFA salt of the title compound (0.077 g, 0.117mmol, 58.5% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.08 (s, 1H), 10.18(s, 1H), 7.37-7.43 (m, 2H), 7.30-7.31 (m, 2H), 7.22 (dd, J=8.85, 2.75Hz, 1H), 7.08-7.14 (m, 1H), 7.00-7.04 (m, 1H), 6.91 (d, J=8.54 Hz, 1H),6.28-6.29 (m, 1H), 3.51-3.62 (m, 11H), 3.24 (br s, 4H). MS (ESI+) m/z545.1 (M+H)⁺.

Example 296N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide

A mixture of Example 36e (0.15 g, 0.326 mmol), 2-(dimethylamino)ethanol(0.029 g, 0.326 mmol), and triphenylphosphine (0.128 g, 0.490 mmol) intetrahydrofuran (3 mL) was stirred at ambient temperature for 10minutes. To this solution was added (E)-di-tert-butyldiazene-1,2-dicarboxylate (0.113 g, 0.490 mmol). The solution wasstirred for three hours at ambient temperature. The solvent was removed,and the residue was purified by preparative HPLC (10-80% acetonitrile in0.1% TFA water) to give the title compound (0.055 g, 0.104 mmol, 31.8%yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.06 (s, 1H), 7.51 (d, J=2.44Hz, 1H), 7.41-7.47 (m, 1H), 7.35-7.37 (m, 2H), 7.23-7.31 (m, 2H),7.06-7.11 (m, 1H), 6.85 (d, J=8.85 Hz, 1H), 3.57 (t, J=6.71 Hz, 2H),3.56 (s, 3H), 3.17 (q, J=7.32 Hz, 1H), 2.25 (m, 2H), 2.13 (s, 6H), 1.25(q, J=7.48 Hz, 3H). MS (ESI+) m/z 531.2 (M+H)⁺.

Example 2974-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 297a (3-bromo-4-(2,4-difluorophenoxy)benzyl)(ethyl)sulfane

Example 297a was prepared according to the procedure used for thepreparation of Example 287d, substituting sodium ethanethiolate forsodium thiomethoxide, to provide the title compound (1.04 g, 99%).

Example 297b2-bromo-1-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene

Example 297b was prepared according to the procedure used for thepreparation of Example 287e, substituting Example 297a for Example 287d,to provide the title compound (1.01 g, 89%).

Example 297c4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 297c was prepared according to the procedure used for thepreparation of Example 287f, substituting Example 297b for Example 287e.Purification by flash chromatography (silica gel, 0 to 2% methanol indichloromethane) afforded the title compound (63 mg, 51%).

Example 297d4-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 297d was prepared according to the procedure used for thepreparation of Example 287g, substituting Example 297c for Example 287f,to provide the title compound (34 mg, 75%). ¹H NMR (300 MHz, DMSO-d₆) □ppm 12.04 (s, 1H) 7.56 (d, J=2.37 Hz, 1H) 7.15-7.48 (m, 5H) 6.99-7.11(m, 1H) 6.87 (d, J=8.14 Hz, 1H) 6.25-6.35 (m, 1H) 4.49 (s, 2H) 3.55 (s,3H) 3.07 (q, J=7.23 Hz, 2H) 1.23 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 459(M+H)⁺.

Example 2984-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 298a2-bromo-1-(2,4-difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene

To a solution of Example 297b (469 mg, 1.20 mmol) in tetrahydrofuran (10mL) was added 60% sodium hydride in mineral oil (240 mg, 6.00 mmol) at0° C. The reaction mixture was stirred at ambient temperature undernitrogen for 10 minutes. Iodomethane (0.750 mL, 12.0 mmol) was added.The reaction mixture was stirred at ambient temperature for 20 hours.The reaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedwith anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by flash chromatography (silica gel, 20 to 40% ethylacetate in heptanes) to provide the title compound (442 mg, 88%).

Example 298b4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 298b was prepared according to the procedure used for thepreparation of Example 287f, substituting Example 298a for Example 287e.Purification by flash chromatography (silica gel, 0 to 2% methanol indichloromethane) afforded the title compound (80 mg, 62%).

Example 298c4-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 298c was prepared according to the procedure used for thepreparation of Example 287g, substituting Example 298b for Example 287fand the reaction time was 16 hours instead of 44 hours, to provide thetitle compound (52 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆) □□ ppm 12.06 (s,1H) 7.71 (d, J=2.44 Hz, 1H) 7.55 (dd, J=8.70, 2.59 Hz, 1H) 7.38-7.48 (m,1H) 7.33 (s, 1H) 7.19-7.31 (m, 2H) 7.02-7.12 (m, 1H) 6.85 (d, J=8.24 Hz,1H) 6.29 (d, J=2.14 Hz, 1H) 3.56 (s, 3H) 2.90 (q, J=7.43 Hz, 2H) 1.77(s, 6H) 1.06 (t, J=7.48 Hz, 3H). MS (ESI+) m/z 487 (M+H)⁺.

Example 2994-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 299a 1-((3-bromo-4-fluorophenyl)sulfonyl)pyrrolidine

To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (1.0 g,3.66 mmol) in 20 mL dichloromethane at 0° C. was added pyrrolidine(0.635 mL, 7.68 mmol). The mixture was stirred at 0° C. for 30 minutesand then at room temperature overnight. The reaction mixture was dilutedwith dichloromethane, washed with 1% HCl solution and water, dried overanhydrous magnesium sulfate, filtered, and concentrated to give thetitle compound (0.86 g, 76% yield)

Example 299b1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)pyrrolidine

A mixture of Example 299a (250 mg, 0.811 mmol), 2,4-difluorophenol (106mg, 0.811 mmol) and cesium carbonate (317 mg, 0.973 mmol) in 5 mLdimethylsulfoxide was heated at 110° C. for 2 hours. Water was added andthe mixture was extracted with ethyl acetate. The organic phase waswashed with water (2×), saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedto give the title compound (278 mg, 82% yield), which was used withoutfurther purification.

Example 299c4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 299b (100 mg, 0.239 mmol), Example 6a (102 mg,0.239 mmol), tetrakis(triphenylphosphine)palladium(0) (13.81 mg, 0.012mmol) and cesium fluoride (109 mg, 0.717 mmol) in 2 mL dimethxoyethaneand 1 mL methanol was heated at 120° C. in a microwave oven (BiotageInitiator) for 40 minutes. The mixture was then treated with 4 N NaOH (1mL) and stirred at ambient temperature for 2 hours. Water was added andthe mixture was extracted with ethyl acetate (2×). The organic phase waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated and theresidue was purified by flash chromatography (silica gel, 60-100% ethylacetate/heptanes gradient) to give the title compound (75 mg, 64.6%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.06 (s, 1H), 12.06 (s, 1H),7.81 (d, J=2.4 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.77-7.72 (m, 1H),7.79-7.72 (m, 1H), 7.47 (ddd, J=11.5, 8.8, 3.0 Hz, 1H), 7.47 (ddd,J=17.8, 10.4, 6.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.43-7.35 (m, 2H), 7.30(t, J=2.8 Hz, 1H), 7.30 (t, J=2.8 Hz, 1H), 7.28-7.09 (m, 1H), 7.17-7.09(m, 1H), 6.98-6.93 (m, 1H), 6.99-6.93 (m, 1H), 6.24 (ddd, J=23.2, 2.6,2.2 Hz, 1H), 6.22 (dd, J=2.6, 2.2 Hz, 1H), 3.57 (s, 3H), 3.57 (s, 3H),3.22-3.09 (m, 4H), 3.19-3.11 (m, 4H), 1.72-1.64 (m, 4H), 1.75-1.61 (m,4H), 1.17 (dd, J=18.8, 11.7 Hz, 1H), 0.87-0.74 (m, 1H). MS (ESI+) m/z464.2 (M+H)⁺.

Example 300N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(dimethylamino)ethanesulfonamide

Example 300 was prepared according to the procedure used for thepreparation of Example 295b, substituting N, N-dimethylamine formorpholine, to provide the TFA salt of the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.07 (s, 1H), 10.18 (s, 1H), 9.86 (br s, 1H),7.37-7.42 (m, 2H), 7.29-7.31 (m, 2H), 7.22 (dd, J=8.54, 2.75 Hz, 1H),7.09-7.14 (m, 1H), 7.01-7.07 (m, 1H), 6.91 (d, J=8.85 Hz, 1H), 6.28 (t,J=2.29 Hz, 1H), 3.62-3.65 (m, 2H), 3.54 (s, 3H), 3.48-3.51 (m, 2H), 2.83(s, 6H). MS (ESI+) m/z 503.1 (M+H)⁺.

Example 301 ethyl4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylateExample 301a ethyl4-(2-bromo-4-(ethylsulfonyl)phenoxy)piperidine-1-carboxylate

Example 301a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 138a for Example 168b,and ethyl 4-hydroxypiperidine-1-carboxylate for cyclopropylmethanol,respectively, to provide the title compound.

Example 301b ethyl4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate

Example 301b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 301a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.04 (s,1H), 7.80-7.83 (m, 2H), 7.44 (d, J=8.54 Hz, 1H), 7.33 (s, 1H), 7.29 (t,J=2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.76-4.81 (m, 1H), 3.99 (q, J=7.02Hz, 2H), 3.57 (s, 3H), 3.24-3.39 (m, 6H), 1.86-1.90 (m, 2H), 1.49-1.53(m, 2H), 1.12-1.16 (M, 6H). MS (ESI+) m/z 488.1 (M+H)⁺.

Example 3024-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 302a1-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfonyl)pyrrolidine

To a solution of cyclopropylmethanol (115 μL, 1.460 mmol) in dioxane (8mL) at room temperature was added sodium hydride (78 mg, 1.947 mmol).After stirring at ambient temperature for 10 minutes, Example 299a (300mg, 0.973 mmol) was added as a solid. The mixture was then heated at 65°C. overnight. Water was added. The mixture was extracted with ethylacetate, washed with water (2×), saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 0-50% ethylacetate/heptanes gradient) to give the title compound (156 mg, 44.5%yield)

Example 302b4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 302a (84 mg, 0.233 mmol), Example 6a (100 mg, 0.233mmol), tetrakis(triphenylphosphine)palladium(0) (13.49 mg, 0.012 mmol)and cesium fluoride (106 mg, 0.700 mmol) in 2 mL dimethoxyethane and 1mL methanol was purged with nitrogen gas and heated at 130° C. undermicrowave conditions (Biotage Initiator) for 40 minutes. The mixture wasthen treated with 4 N NaOH (1 mL) and stirred at room temperature for 2hours. Water was added and the mixture was extracted with ethyl acetate,washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was absorbedon silica gel and purified by flash chromatography (silica gel, 0-10%methanol/dichloromethane gradient) to give the title compound (64 mg,64.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.10-11.92 (m, 1H),7.77-7.70 (m, 2H), 7.37 (s, 1H), 7.30 (dd, J=6.9, 4.1 Hz, 2H), 6.17-6.03(m, 1H), 3.97 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.14 (t, J=6.7 Hz, 4H),1.71-1.64 (m, 4H), 1.15-1.08 (m, 1H), 0.50-0.44 (m, 2H), 0.30-0.24 (m,2H). MS (ESI+) m/z 482.2 (M+H)⁺.

Example 3034-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 303a1-(4-(2-bromo-4-(ethylsulfonyl)phenoxy)piperidin-1-yl)ethanone

Example 303a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168b for Example 138a,and substituting 1-(4-hydroxypiperidin-1-yl)ethanone forcyclopropylmethanol, respectively, to provide the title compound.

Example 303b4-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 303b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 303a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.04 (s,1H), 7.80-7.84 (m, 2H), 7.45 (d, J=8.54 Hz, 1H), 7.33 (s, 1H), 7.29 (t,J=2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.81-4.84 (m, 1H), 3.57 (s, 3H),3.24-3.39 (m, 6H), 2.09 (s, 3H), 1.49-1.53 (m, 2H), 1.12-1.16 (m, 3H).MS (ESI+) m/z 458.2 (M+H)⁺.

Example 3044-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]benzonitrile

Example 304 was prepared according to the procedure used for thepreparation of Example 138b, substituting Example 168c for Example 138a,and 4-cyanophenol for 2,4-difluorophenol, respectively, to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.09 (s, 1H), 8.00 (d,J=2.44 Hz, 1H), 7.92 (dd, J=8.54, 2.54 Hz, 1H), 7.79-7.82 (m, 2H), 7.39(s, 1H), 7.35 (d, J=8.54 Hz, 1H), 7.29 (t, J=2.75 Hz, 1H), 7.14-7.17 (m,2H), 6.22-6.23 (m, 1H), 3.54 (s, 3H), 3.38 (q, J=7.32 Hz, 2H), 1.17 (t,J=7.32 Hz, 3H). MS (ESI+) m/z 434.2 (M+H)⁺.

Example 3054-[2-(cyclopropylmethoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 305a 1-(3-bromo-4-fluorophenylsulfonyl)indoline

A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (Aldrich)(2.53 g, 8.33 mmol), indoline (0.99 g, 8.33 mmol),N,N-diisopropylethylamine (1.60 mL, 9.16 mmol) and tetrahydrofuran (20mL) was stirred at ambient temperature for 16 hours. The reactionmixture was partitioned between water and ethyl acetate. The aqueouslayer was extracted twice with additional ethyl acetate. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated to afford abrown oil which solidified upon standing. The crude product wasrecrystallized from ether/heptane to afford the title compound (1.99 g,5.59 mmol, 67% yield).

Example 305b 1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl)indoline

Example 305b was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol and substituting Example 305a for Example 2a toafford the title compound.

Example 305c4-(2-(cyclopropylmethoxy)-5-(indolin-1-ylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 305c was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 305b for Example 6b toafford the title compound.

Example 305d4-(2-(cyclopropylmethoxy)-5-(indolin-1-ylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 305d was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 305c for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ 0.24 (tt, J=13.4,6.6 Hz, 2H) 0.35-0.50 (m, 2H) 1.01-1.18 (m, 1H) 2.90 (t, J=8.3 Hz, 2H)3.54 (s, 3H) 3.90 (t, J=8.4 Hz, 2H) 3.92 (d, J=6.8 Hz, 2H) 5.80-5.86 (m,1H) 7.04 (td, J=7.4, 1.0 Hz, 1H) 7.14-7.36 (m, 5H) 7.50 (d, J=8.0 Hz,1H) 7.66 (d, J=2.4 Hz, 1H) 7.77 (dd, J=8.7, 2.5 Hz, 1H) 12.02 (bs, 1H).MS (ESI+) m/z 476 [M+H]⁺.

Example 3064-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 306a (3-bromo-4-(2,4-difluorophenoxy)benzyl)(phenyl)sulfane

Example 306a was prepared according to the procedure used for thepreparation of Example 287d, substituting sodium thiophenoxide forsodium thiomethoxide, to provide the title compound (815 mg, 100%).

Example 306b2-bromo-1-(2,4-difluorophenoxy)-4-(phenylsulfonylmethyl)benzene

Example 306b was prepared according to the procedure used for thepreparation of Example 287e, substituting Example 306a for Example 287d,to provide the title compound (867 mg, 99%).

Example 306c4-(2-(2,4-difluorophenoxy)-5-(phenylsulfonylmethyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 306c was prepared according to the procedure used for thepreparation of Example 287f, substituting Example 306b for Example 287e.Purification by flash chromatography (silica gel, 0 to 2% methanol indichloromethane) afforded the title compound (51 mg, 52%).

Example 306d4-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 306d was prepared according to the procedure used for thepreparation of Example 287g, substituting Example 306c for Example 287f,to provide the title compound (30 mg, 80%). ¹H NMR (300 MHz, DMSO-d₆) □□ppm 12.02 (s, 1H) 7.69-7.81 (m, 3H) 7.55-7.67 (m, 2H) 7.34-7.46 (m, 1H)7.20-7.29 (m, 2H) 6.98-7.18 (m, 4H) 6.80 (d, J=8.48 Hz, 1H) 6.09 (dd,J=2.37, 1.70 Hz, 1H) 4.71 (s, 2H) 3.52 (s, 3H). MS (ESI+) m/z 507(M+H)⁺.

Example 3074-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 307a1-((3-bromo-4-((2,2-difluorocyclopropyl)methoxy)phenyl)sulfonyl)pyrrolidine

Example 307a was prepared according to the procedure used for thepreparation of Example 302a, substituting(2,2-difluorocyclopropyl)methanol for cyclopropylmethanol, to providethe title compound.

Example 307b4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 307b was prepared according to the procedure used for thepreparation of Example 302b, substituting 307a for 302a, to provide thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.05 (s, 1H), 12.05 (s,1H), 7.76 (tt, J=6.9, 3.5 Hz, 2H), 7.81-7.71 (m, 2H), 7.35 (d, J=8.4 Hz,2H), 7.38-7.27 (m, 3H), 7.30 (t, J=2.6 Hz, 1H), 6.12 (dd, J=2.5, 1.6 Hz,1H), 6.12 (dd, J=2.5, 1.6 Hz, 1H), 4.21 (dt, J=18.8, 9.6 Hz, 2H), 3.57(s, 3H), 3.57 (s, 3H), 3.15 (t, J=6.7 Hz, 4H), 3.15 (t, J=6.7 Hz, 4H),2.21-2.04 (m, 1H), 2.19-1.98 (m, 1H), 1.74-1.57 (m, 5H), 1.77-1.57 (m,5H), 1.52-1.36 (m, 1H), 1.53-1.38 (m, 1H). MS (ESI+) m/z 464.2 (M+H)⁺.

Example 3084-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 308a 1-((3-bromo-4-fluorophenyl)sulfonyl)-3,3-difluoroazetidine

To a suspension of 3,3-difluoroazetidine hydrochloric acid (0.947 g,7.31 mmol) in 20 mL dichloromethane at 0° C. was addedN-ethyl-N-isopropylpropan-2-amine (2.80 mL, 16.1 mmol) followed by theaddition of a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride(2.0 g, 7.3 mmol) in 4 mL dichloromethane. The mixture was stirred atroom temperature overnight and then heated at 55° C. for 5 hours,diluted with dichloromethane, washed with water, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated and theresidue was purified by flash chromatography (silica gel, 10-50% ethylacetate/heptanes gradient) to give the title compound (1.5 g, 62.1%yield)

Example 308b1-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfonyl)-3,3-difluoroazetidine

Example 308b was prepared according to the procedure used for thepreparation of Example 302a, substituting Example 308a for Example 299ato provide the title compound.

Example 308c4-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 308c was prepared according to the procedure used for thepreparation of Example 302b, substituting Example 308b for Example 302ato provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.04 (s,1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.40 (s, 1H),7.36 (d, J=8.8 Hz, 1H), 7.29 (t, J=2.7 Hz, 1H), 6.12-6.08 (m, 1H), 4.26(t, J=12.7 Hz, 4H), 4.01 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 1.14-1.08 (m,1H), 0.50-0.43 (m, 2H), 0.30-0.25 (m, 2H). MS (DCI+) m/z 491.4(M+CH₃CN)⁺.

Example 3094-{2-[2-(2-hydroxyethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 304 was prepared according to the procedure used for thepreparation of Example 138b, substituting 2-(2-hydroxyethyl)phenol for2,4-difluorophenol, to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.11 (s, 1H), 8.00 (d, J=2.44 Hz, 1H), 7.85 (dd, J=8.85,2.44 Hz, 1H), 7.45 (s, 1H), 7.36 (dd, J=7.63, 1.53 Hz, 1H), 7.32 (t,J=2.9 Hz, 1H), 7.24-7.28 (m, 1H), 7.14-7.18 (m, 1H), 6.98-7.01 (m, 1H),6.89 (d, J=8.54 Hz, H), 6.29-6.31 (m, 1H), 3.57 (s, 3H), 3.46 (t, J=7.02Hz, 2H), 3.25 (s, 3H), 2.63 (t, J=7.02 Hz, 2H). MS (ESI+) m/z 439.1(M+H)⁺.

Example 3104-[2-(cyclopropylmethoxy)-5-{[3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 310a1-(3-bromo-4-fluorophenylsulfonyl)-N,N-dimethylpyrrolidin-3-amine

A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (Combi-blocks)(250 mg, 0.91 mmol), N,N-dimethylpyrrolidin-3-amine (218 mg, 1.9 mmol)in tetrahydrofuran (5.7 mL) was stirred at ambient temperature for 16hours. The solvent was evaporated and residue was purified by flashchromatography (silica gel, dichloromethane/gradient with MeOH) toafford the title compound (220 mg, 69% yield).

Example 310b1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl-N,N-dimethyl-3-amine

Example 310b was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol and substituting Example 310a for Example 2a toafford the title compound.

Example 310c4-(2-(cyclopropylmethoxy)-5-(3-(dimethylamino)pyrrolidin-1-ylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 310c was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 310b for Example 6b, toafford the title compound.

Example 310d4-(2-(cyclopropylmethoxy)-5-(3-(dimethylamino)pyrrolidin-1-ylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 310d was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 310c for Example 6c, toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 0.25-0.31 (m,2H) 0.44-0.51 (m, 2H) 1.06-1.17 (m, 1H) 1.45-1.59 (m, 1H) 1.86-1.97 (m,1H) 2.04 (s, 6H) 2.52-2.57 (m, 1H) 2.82-2.90 (m, 1H) 3.07-3.18 (m, 1H)3.25-3.28 (m, 1H) 3.34-3.42 (m, 1H) 3.57 (s, 3H) 3.98 (d, J=6.78 Hz, 2H)6.12 (t, J=2.71, 2.03 Hz, 1H) 7.28-7.33 (m, 2H) 7.35 (s, 1H) 7.71-7.79(m, 2H) 12.04 (s, 1H). MS (ESI+) m/z 471 [M+H]⁺.

Example 3114-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 311a 5-bromo-6-(2,4-difluorophenoxy)nicotinic acid

5-bromo-6-chloronicotinic acid (3 g, 12.69 mmol), 2,4-difluorophenol(3.30 g, 25.4 mmol) and cesium carbonate (16.54 g, 50.8 mmol) werecombined in DMSO (25.4 mL), heated at 100° C. for 6 hours, cooled,diluted with 150 mL of iced water and the pH was adjusted to pH 3 with12M HCl. The resulting solid was collected by filtration, washed withcold water and dried to constant mass to afford the title compound (2.84g, 64%).

Example 311b (5-bromo-6-(2,4-difluorophenoxy)pyridin-3-yl)methanol

The product from Example 311a (1.0 g, 3.03 mmol) and boranetetrahydrofuran complex (6.06 mL, 6.06 mmol) were combined intetrahydrofuran (15.15 mL) and heated at 50° C. for 2 hours, cooled,treated with 10 mL of methanol, heated at 50° C. for 1 hour, cooled andconcentrated. The residue was partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride, dried (Na₂SO₄), filtered, and concentrated. Purification bychromatography (silica gel, 0-50% ethyl acetate in heptanes) affordedthe title compound (0.73 g, 76%).

Example 311c 3-bromo-5-(bromomethyl)-2-(2,4-difluorophenoxy)pyridine

A solution of the product from Example 311b (0.73 g, 2.309 mmol) indichloromethane (11.55 mL) under nitrogen was treated dropwise withtribromophosphine (0.218 mL, 2.309 mmol), stirred for one hour atambient temperature and poured into ice water and the pH was adjusted topH 9 by addition of solid sodium bicarbonate added portionwise. Anemulsion formed that was partially removed by filtration. The aqueouslayer was extracted with dichloromethane and the organics were combined,washed with saturated aqueous sodium chloride, dried (Na₂SO₄) filtered,and concentrated to afford the title compound (0.75 g, 86%).

Example 311d3-bromo-2-(2,4-difluorophenoxy)-5-(methylthiomethyl)pyridine

The product from Example 311c (0.75 g, 1.979 mmol) and sodiumthiomethoxide (0.139 g, 1.979 mmol) were combined in dimethylformamide(3.96 mL), stirred for 4 hours at ambient temperature, and partitionedinto ethyl acetate and cold water. The organic layer was washed withsaturated aqueous sodium chloride, dried (Na₂SO₄), filtered, andconcentrated to afford the title compound (0.66 g, 96%).

Example 3Ile3-bromo-2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)pyridine

A solution of the product from Example 311d (0.66 g, 1.906 mmol) at 0°C. in methanol (7.33 mL) was treated with a solution of Oxone (2.461 g,4.00 mmol) in water (7.33 mL), stirred at ambient temperature for twohours and partitioned between ethyl acetate and water. The organic layerwas washed with saturated aqueous sodium chloride, dried (Na₂SO₄),filtered, and concentrated. Purification by chromatography (silica gel,0-5% methanol in dichloromethane) afforded the title compound (0.433 g,60%).

Example 311f4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)pyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

The product from Example 311e (0.075 g, 0.198 mmol), the product fromExample 6a (0.085 g, 0.198 mmol), ),tris(dibenzylideneacetone)dipalladium(0) (5.45 mg, 5.95 μmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (5.80 mg,0.020 mmol) and potassium phosphate (0.126 g, 0.595 mmol) were combinedand sparged with argon for 15 minutes. Meanwhile a solution of 4:1dioxane/water (2 mL) was sparged with nitrogen for 15 minutes andtransferred by syringe into the reaction vessel under argon. The mixturewas stirred for 2 hours at 60° C. and partitioned between ethyl acetateand water. The organic layer was washed with saturated aqueous sodiumchloride, dried (Na₂SO₄), treated with 3-mercaptopropyl functionalizedsilica gel, filtered, and concentrated. Purification by trituration indichloromethane afforded the title compound (0.083 g, 70%).

Example 311g4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The product from Example 311f (0.083 g, 0.138 mmol), potassium hydroxide(0.194 g, 3.46 mmol) and N,N,N-trimethylhexadecan-1-aminium bromide(2.52 mg, 6.92 μmol) were combined in dioxane (1.8 mL)/water (0.9 mL)and heated at 100° C. for 4 hours, cooled, and partitioned into ethylacetate adjusting the pH to 7 with 1 M HCl. The organic layer was washedwith saturated aqueous sodium chloride, dried (Na₂SO₄), filtered, andconcentrated. Purification by chromatography (silica gel, 0-4% methanolin dichloromethane) afforded the title compound (0.035 g, 57%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.14 (s, 1H) 8.03 (dd, J=22.74, 2.29 Hz, 2H)7.30-7.51 (m, 4H) 7.03-7.17 (m, 1H) 6.39 (d, J=2.14 Hz, 1H) 4.57 (s, 2H)3.60 (s, 3H) 3.00 (s, 3H). MS (ESI+) m/z 446 [M+H]⁺.

Example 312 tert-butyl4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylateExample 312a tert-butyl4-(2-bromo-4-(ethylsulfonyl)phenoxy)piperidine-1-carboxylate

Example 312a was prepared according to the procedure used for thepreparation of Example 158, substituting Example 168b for Example 138a,and tert-butyl 4-hydroxypiperidine-1-carboxylate forcyclopropylmethanol, respectively, to provide the title compound.

Example 312b tert-butyl4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate

Example 312b was prepared according to the procedure used for thepreparation of Example 95d, substituting Example 312a for Example 95c,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.02 (s,1H), 7.79-7.842 (m, 2H), 7.42 (d, J=8.54 Hz, 1H), 7.31 (s, 1H), 7.27 (t,J=2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.74-4.78 (m, 1H), 3.55 (s, 3H),3.14-3.32 (m, 6H), 1.82-1.87 (m, 2H), 1.43-1.51 (m, 2H), 1.35 (s, 9H),1.12 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 515.9 (M+H)⁺.

Example 3134-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-phenylbenzenesulfonamideExample 313a 3-bromo-4-fluoro-N-phenylbenzenesulfonamide

Example 313a was prepared according to the procedure used for thepreparation of Example 305a, substituting aniline for indoline. Thecrude product was purified by flash chromatography (silica gel, elutedwith 10% ethyl acetate in heptane) to afford title compound

Example 313b 3-bromo-4-(cyclopropylmethoxy)-N-phenylbenzenesulfonamide

Example 313b was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol and substituting Example 313a for Example 2a toafford the title compound.

Example 313c4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-phenylbenzenesulfonamide

Example 313c was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 313b for Example 6b toafford the title compound.

Example 313d4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-phenylbenzenesulfonamide

Example 313d was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 313c for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ 0.25 (tt, J=15.6,7.6 Hz, 2H) 0.39-0.50 (m, 2H) 1.01-1.18 (m, 1H) 3.55 (s, 3H) 3.91 (d,J=6.8 Hz, 2H) 5.91 (dd, J=2.8, 2.0 Hz, 1H) 7.01-7.15 (m, 3H) 7.15-7.34(m, 5H) 7.65-7.72 (m, 2H) 10.12 (s, 1H) 12.02 (bs, 1H). MS (ESI+) m/z450 [M+H]⁺.

Example 3144-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 314a 4-bromo-1-(cyclopropylmethoxy)-2-iodobenzene

A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol),bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50° C.overnight. Water was added and the mixture was extracted with ethylacetate. The organic phase was washed with water, saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated to the provide title compound (5.84 g, 99%yield).

Example 314b4-(5-bromo-2-(cyclopropylmethoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 6a (1.1 g, 2.57 mmol), Example 314a (0.907 g, 2.57mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.060 g, 0.21 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.094 g,0.103 mmol), and potassium phosphate (1.635 g, 7.70 mmol) in 15 mLdioxane and 5 mL water was purged with nitrogen gas and then heated at55° C. for 3 hours. Saturated aqueous sodium chloride was added and themixture was extracted with ethyl acetate (2×). The combined organicphases were dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 0-80% ethyl acetate/heptanes gradient) to give the title compound(1.24 g, 92% yield).

Example 314c4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 314b (100 mg, 0.190 mmol), potassiumtrifluoro(pyrrolidin-1-ylmethyl)borate (36.2 mg, 0.190 mmol),palladium(II) acetate (2.55 mg, 0.011 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (10.85 mg,0.023 mmol), and cesium carbonate (185 mg, 0.569 mmol) in 4 mLdioxane/water (9:1) was purged with nitrogen gas and then heated undermicrowave conditions (Biotage Initiator) at 140° C. for 40 minutes. Thereaction mixture was then treated with 2 mL of 4 N NaOH and heated in amicrowave oven (Biotage Initiator) at 100° C. for 30 minutes. Water wasadded. The mixture was extracted with ethyl acetate, washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated and the residue waspurified by flash chromatography (silica gel, 2-14%methanol/dichloromethane gradient) to give the title compound (8.0 mg,11% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.93 (s, 1H), 7.29-7.17 (m,4H), 7.00 (d, J=8.4 Hz, 1H), 6.11 (dd, J=2.6, 2.2 Hz, 1H), 3.81 (d,J=6.7 Hz, 2H), 3.56 (s, 3H), 3.53 (s, 2H), 2.43 (s, 4H), 1.68 (s, 4H),1.13-0.98 (m, 1H), 0.48-0.36 (m, 2H), 0.26-0.16 (m, 2H). MS (ESI+) m/z378.0 (M+H)⁺.

Example 3154-[2-(cyclopropylmethoxy)-5-(pyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A suspension of Example 314b (100 mg, 0.190 mmol), pyridin-3-ylboronicacid (23.31 mg, 0.190 mmol), sodium carbonate (60.3 mg, 0.569 mmol), andtris(dibenzylideneacetone)-dipalladium(0) (15.48 mg, 0.019 mmol) in 4 mLdioxane-water (3:1) was heated under nitrogen under microwave conditions(Biotage Initiator) at 120° C. for 30 minutes. The reaction mixture wasthe treated with 1 mL aqueous 4 N NaOH and heated at 120° C. undermicrowave conditions again for 30 minutes. The mixture was diluted withwater and extracted with ethyl acetate (2×), washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated and the residue was purified byflash chromatography (silica gel, 0-10% methanol/dichloromethanegradient) to give the title compound (53 mg, 75% yield). ¹H NMR (300MHz, DMSO-d₆) δ ppm 11.95 (s, 1H), 8.90 (dd, J=2.4, 0.7 Hz, 1H),8.56-8.49 (m, 1H), 8.07 (ddd, J=8.0, 2.4, 1.7 Hz, 1H), 7.71-7.64 (m,2H), 7.45 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.34 (s, 1H), 7.26 (t, J=2.7Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.18 (dd, J=2.6, 2.2 Hz, 1H), 3.91 (d,J=6.7 Hz, 2H), 3.58 (s, 3H), 1.15-1.04 (m, 1H), 0.49-0.42 (m, 2H),0.28-0.21 (m, 2H). MS (ESI+) m/z 372.2 (M+H)⁺.

Example 3164-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 316 was prepared according to the procedure used for thepreparation of Example 314c, substituting potassiumtrifluoro(morpholinomethyl)borate for potassiumtrifluoro(pyrrolidin-1-ylmethyl)borate to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.01 (s, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.43(d, J=8.4 Hz, 1H), 7.28 (dd, J=4.9, 2.0 Hz, 2H), 7.18 (d, J=8.5 Hz, 1H),6.21-6.14 (m, 1H), 4.32 (s, 2H), 3.97 (d, J=12.4 Hz, 2H), 3.89 (d, J=6.7Hz, 2H), 3.63 (d, J=11.7 Hz, 2H), 3.57 (s, 3H), 3.29 (d, J=12.8 Hz, 2H),3.10 (d, J=10.4 Hz, 2H), 1.17-1.02 (m, 1H), 0.51-0.42 (m, 2H), 0.28-0.21(m, 2H). ). MS (ESI+) m/z 394.0 (M+H)⁺.

Example 3174-{5-(ethylsulfonyl)-2-[3-(hydroxymethyl)phenoxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 317 was prepared according to the procedure used for thepreparation of Example 138b, substituting 3-(hydroxymethyl)phenol for2,4-difluorophenol, and Example 168c for Example 138a, respectively, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 12.07 (s, 1H),7.93 (d, J=2.44 Hz, 1H), 7.83 (dd, J=8.7, 2.29 Hz, 1H), 7.42 (s, 1H),7.35 (t, J=7.93 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.15 (d, J=7.63 Hz,1H), 7.02-7.05 (m, 2H), 6.97 (dd, J=7.93, 2.14 Hz, 1H), 6.26 (t, J=2.44Hz, 1H), 4.48 (s, 2H), 3.57 (s, 3H), 3.34 (q, J=7.32 Hz, 2H), 1.15 (t,J=7.32 Hz, 3H). MS (ESI+) m/z 439.0 (M+H)⁺.

Example 3184-[2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 318 was prepared according to the procedure used for thepreparation of Example 315, substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole forpyridin-3-ylboronic acid to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.93 (s, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.77 (dd, J=6.3,0.6 Hz, 1H), 7.48 (q, J=2.2 Hz, 2H), 7.28-7.24 (m, 2H), 7.06 (d, J=8.3Hz, 1H), 6.21-6.05 (m, 1H), 3.83 (d, J=4.9 Hz, 5H), 3.56 (d, J=5.7 Hz,3H), 1.06-1.02 (m, 1H), 0.46-0.40 (m, 2H), 0.24-0.19 (m, 2H). ). MS(ESI+) m/z 375.2 (M+H)⁺.

Example 3194-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 319a 1-(3-bromo-4-(2,4-difluorophenoxy)phenylsulfonyl)indoline

Example 319a was prepared according to the procedure used for thepreparation of Example 2b, substituting 2,4-difluorophenol for phenoland substituting Example 305a for Example 2a, to provide the titlecompound.

Example 319b4-(2-(2,4-difluorophenoxy)-5-(indolin-1-ylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 319b was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 319a for Example 6b, toafford the title compound.

Example 319c4-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 319c was prepared according to the procedure used for thepreparation of Example 6d, and substituting Example 319b for Example 6cto afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ 2.92 (t, J=8.3Hz, 2H) 3.55 (s, 3H) 3.93 (t, J=8.3 Hz, 2H) 5.98 (dd, J=2.8, 1.9 Hz, 1H)6.91 (dd, J=9.3, 1.0 Hz, 1H) 6.98-7.29 (m, 6H) 7.34-7.58 (m, 3H)7.74-7.91 (m, 2H) 12.08 (bs, 1H). MS (ESI+) m/z 534 [M+H]⁺.

Example 320N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 320a 5-bromo-1,4-dimethyl-3-nitropyridin-2(1H)-one

Example 320a was prepared according to the procedure used for thepreparation of Example 1e, substituting Example 1d for5-bromo-4-methyl-3-nitropyridin-2-ol, to provide the title compound.

Example 320b 3-amino-5-bromo-1,4-dimethylpyridin-2(1H)-one

Example 320b was prepared according to the procedure used for thepreparation of Example 7b, substituting Example 320a for Example 7a, toprovide the title compound.

Example 320c 4-bromo-6-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 320b (1 g, 4.61 mmol), acetic anhydride (1.304 mL, 13.82 mmol),and potassium acetate (0.543 g, 5.53 mmol) were stirred in toluene (25mL) for 18 hours. Isoamyl nitrite (0.930 mL, 6.91 mmol) was addeddropwise and the solution heated at 80° C. for 24 hours. The solutionwas cooled, water added, and the aqueous extracted with ethyl acetate.The combined organics were washed with saturated aqueous sodiumchloride, dried (anhydrous magnesium sulfate), filtered, andconcentrated. The residue was triturated with 30% ethyl acetate inhexanes to afford 0.415 g of the title compound.

Example 320d4-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 320c (0.228 g, 1.000 mmol) in dimethylformamide (5 mL) wastreated with sodium hydride (0.060 g, 1.500 mmol). The reaction mixturewas stirred at ambient temperature for 10 minutes. To this solution wasadded (2-(chloromethoxy)ethyl)trimethylsilane (0.200 g, 1.200 mmol). Thereaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was partitioned between ethyl acetate and water, andthe organic phase separated, washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, ethyl acetate/heptane gradient) to afford the title compound (0.301g, 0.840 mmol, 84% yield).

Example 320e4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 320e was prepared according to the procedure used for thepreparation of Example 138a, substituting Example 320d for2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for Example6a, respectively, to provide the title compound.

Example 320fN-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide

A mixture of Example 320e (0.1 g, 0.201 mmol), ethanesulfonyl chloride(0.077 g, 0.602 mmol), and triethylamine (0.081 g, 0.802 mmol) indichloromethane was stirred for 2 hours at room temperature. The solventwas removed, and the residue was purified by flash chromatography onsilica gel (4:1 ethyl acetate/hexanes) to give the title compound (0.11g, 0.161 mmol, 80% yield).

Example 320gN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 320f in dichloromethane (3 mL) was treated with2,2,2-trifluoroacetic acid (1.837 g, 16.11 mmol). The reaction mixturewas stirred for 16 hours at ambient temperature. The solvent wasremoved, and the residue was put on high vacuum for 1 hour. It was thentreated with dioxane (5 mL) and 2.0 N sodium hydroxide (1.611 mL, 3.22mmol). The reaction mixture was heated at 85° C. for 2 hours. Aftercooling, the reaction mixture was partitioned between 0.1% HCl and ethylacetate. The aqueous layer was extracted with additional ethyl acetatetwice. The combined organic layers were washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was then purified by reverse phase preparativeHPLC (10-80% acetonitrile in 0.1% TFA water) to afford the TFA salt ofthe title compound (0.055 g, 0.119 mmol, 74.1% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.80 (s, 1H), 7.86 (s, 1H), 7.36-7.42 (m, 3H), 7.22 (dd,J=8.85, 2.75 Hz, 1H), 7.13-7.15 (m, 1H), 6.99-7.04 (m, 1H), 6.92 (d,J=8.85 Hz, H), 3.56 (s, 3H), 3.13 (t, J=7.32 Hz, 2H), 1.23 (t, J=7.32Hz, 3H). MS (ESI+) m/z 461.0 (M+H)⁺.

Example 3214-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-oneExample 321a2-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Example 287e (1.13 g, 3 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.52 g, 6mmol), potassium acetate (1.18 g, 12 mmol), andbis(triphenylphosphine)palladium(II) chloride (0.126 g, 0.18 mmol) werecombined in a 20-mL microwave vial and sparged with nitrogen for 30minutes. To this mixture was added nitrogen-sparged dioxane (15 mL). Thereaction mixture was heated at 90° C. for 8 hours. The reaction mixturewas partitioned between water and ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, treated with 3-mercaptopropyl-functionalized silica gel,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0 to 10% ethyl acetate in dichloromethane)and then triturated with heptane to provide the title compound (0.64 g,50%).

Example 321b4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 320d (0.04 g, 0.112 mmol), Example 321a (0.052 g, 0.123 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.0031 g, 3.35 μmol),(1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane(0.0033 g, 0.011 mmol) and sodium carbonate (0.051 g, 0.48 mmol) werecombined in a 5-mL microwave vial and sparged with nitrogen for 30minutes. To this mixture was added nitrogen-sparged dioxane (0.8 mL) andwater (0.2 mL). The reaction mixture was stirred at 60° C. for 4.5hours. The reaction mixture was cooled to ambient temperature and thenpartitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, treated with3-mercaptopropyl-functionalized silica gel, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 0 to 10% methanol indichloromethane) to provide the title compound (0.06 g, 93%).

Example 321c4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

Example 321b (0.06 g, 0.104 mmol) was treated with 2,2,2-trifluoroaceticacid (2 mL, 26.1 mmol), stirred at ambient temperature for 30 minutesand then concentrated to dryness. The residue was purified by reversephase HPLC (C18, CH₃CN/water (0.1% TFA), 20-80%) to provide the titlecompound (0.03 g, 65%). ¹H NMR (400 MHz, DMSO-d₆) □ ppm 7.91 (s, 1H),7.60 (d, J=2.14 Hz, 1H), 7.42 (m, 3H), 7.29 (m, J=9.23, 9.23, 5.65 Hz,1H), 7.09 (m, 1H), 6.89 (d, J=8.54 Hz, 1H), 4.53 (s, 2H), 3.58 (s, 3H),2.96 (s, 3H). MS (ESI+) m/z 446.1 (M+H)⁺.

Example 3224-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-oneExample 322a ethyl(4-fluorophenyl)sulfane

Triethylamine (5.44 mL, 39 mmol) was added to a solution of4-fluorobenzenethiol (5 g, 39 mmol) and iodoethane (3.78 mL, 46.8 mmol)in tetrahydrofuran (50 mL). The resulting mixture was stirred at ambienttemperature for 2 hours and then filtered. The filtrate wasconcentrated, triturated with hexane, and dried under vacuum to affordthe title compound (4.8 g, 76%).

Example 322b 1-(ethylsulfonyl)-4-fluorobenzene

Example 322a (5 g, 32 mmol) in dichloromethane (200 mL) was treated with3-chloroperoxybenzoic acid (14.3 g, 70.4 mmol) and stirred at ambienttemperature for 6 hours. The solid formed during the reaction mixturewas removed by filtration and washed with additional dichloromethane.The combined filtrate was washed with 10% aqueous sodium hydroxidesolution (50 mL, twice) and saturated aqueous sodium bicarbonatesolution, dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 15% ethyl acetate in petroleum ether) to afford the title compound(4.6 g, 76%).

Example 322c 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene

Example 322b (1 g, 5.31 mmol) in sulfuric acid (6 mL, 113 mmol) wastreated with N-bromosuccinimide (1.04 g, 5.84 mmol), stirred at ambienttemperature for 6 hours and then at 50° C. for 16 hours. The reactionmixture was then poured into ice water and the resulting solid wascollected by filtration, washed with cold water three times, and driedin a vacuum oven for 16 hours. The solid was then purified by flashchromatography (silica gel, 9-20% ethyl acetate in petroleum ether) toafford the title compound (1.1 g, 78%).

Example 322d2-(5-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.665 g,2.62 mmol), Example 322c (0.5 g, 1.9 mmol), potassium acetate (0.367 g,3.74 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.041 g,0.056 mmol) were combined in an argon-sparged mixture of dioxane (10mL)/dimethyl sulfoxide (0.3 mL) and heated at 90° C. under argon for 24hours. The reaction mixture was partitioned between ethyl acetate andwater and filtered through a plug of Celite to remove elementalpalladium. The layers were separated and the organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, treated with 3-mercaptopropyl-functionalized silica gel for 15minutes, filtered, and concentrated. The residue was triturated in aminimal amount of heptane/diethyl ether (20:1) and filtered to givecrude product. This material was then dissolved in ethyl acetate,treated again with 3-mercaptopropyl-functionalized silica gel, filtered,and concentrated. The residue was recrystallized from heptane/ethylacetate (9:1) to afford the title compound (0.3 g, 77%).

Example 322e4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 322e was prepared according to the procedure used for thepreparation of Example 321b, substituting Example 322d for Example 321a,to provide the title compound (0.0635 g, 55%).

Example 322f4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 322e (0.0635 g, 0.136 mmol), 2,4-difluorophenol (0.021 g, 0.164mmol) and cesium carbonate (0.089 g, 0.273 mmol) were combined in a 4-mLvial with dimethyl sulfoxide (1.5 mL), stirred at 60° C. for 8 hours andthen at ambient temperature for 16 hours. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 0 to 8% methanol indichloromethane) to provide the title compound (0.0574 g, 73%).

Example 322g4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 322g was prepared according to the procedure used for thepreparation of Example 321c, substituting Example 322f for Example 321b,to provide the title compound (0.0299 g, 67%). ¹H NMR (400 MHz, DMSO-d₆)□ ppm 7.96 (d, J=2.14 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J=8.70, 2.29 Hz,1H), 7.54 (m, 3H), 7.20 (m, 1H), 7.00 (d, J=8.85 Hz, 1H), 3.61 (s, 3H),3.35 (q, J=7.32 Hz, 2H), 1.15 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 446.2(M+H)⁺.

Example 3234-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-oneExample 323a4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Cyclopropylmethanol (0.018 g, 0.25 mmol) in dioxane (0.75 mL) wastreated with sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol)and stirred at ambient temperature for 10 minutes. A solution of Example322e (0.0683 g, 0.147 mmol) in dioxane (0.75 mL) was added and themixture was stirred at 60° C. for 8 hours and then at ambienttemperature for 16 hours. Additional cyclopropylmethanol (0.018 g, 0.249mmol) and sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) wereadded and the mixture was heated at 70° C. for 9 hours. The reactionmixture was cooled to ambient temperature and then partitioned betweenethyl acetate and water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0 to 30% ethyl acetate in dichloromethane)to provide the title compound (0.0685 g, 90%).

Example 323b4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one

Example 323b was prepared according to the procedure used for thepreparation of Example 321c, substituting Example 323a for Example 321b,to provide the title compound (0.0302 g, 59%). ¹H NMR (400 MHz, DMSO-d₆)□ ppm 14.07 (s, 1H), 7.85 (dd, J=8.70, 2.29 Hz, 1H), 7.80 (d, J=2.14 Hz,1H), 7.78 (m, 1H), 7.41 (s, 1H), 7.34 (d, J=8.54 Hz, 1H), 4.01 (d,J=7.02 Hz, 2H), 3.60 (s, 3H), 3.29 (q, J=7.32 Hz, 2H), 1.13 (t, J=7.32Hz, 3H), 1.06 (m, 1H), 0.45 (m, 2H), 0.27 (m, 2H). MS (ESI+) m/z 388.2(M+H)⁺.

Example 324N-[2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 324a 4-bromo-5-(2,4-difluorophenoxy)-2-nitrobenzoic acid

Example 324a was prepared according to the procedure used for thepreparation of Example 7a, substituting 4-bromo-5-fluoro-2-nitrobenzoicacid for 2-bromo-1-fluoro-4-nitrobenzene (Combi Blocks) and substituting2,4-difluorophenol for phenol to afford the title compound.

Example 324b methyl 4-bromo-5-(2,4-difluorophenoxy)-2-nitrobenzoate

Oxalyl chloride (1.4 mL, 16.6 mmol) was added dropwise to a 0° C.suspension of Example 324a (5.47 g, 14.6 mmol) and dichloromethane (65mL). 3 drops dimethylformamide was added and the reaction mixture wasstirred at ambient temperature for 2 hours. After cooling to 0° C.,methanol (12 mL, 296 mmol) was added dropwise. The solution was stirredfor 15 minutes at 0° C. and for 2.5 hours at ambient temperature. Thesolution was diluted with dichloromethane and was washed with water,saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered and concentrated to affordthe title compound (5.42 g, 96% yield).

Example 324c methyl 2-amino-4-bromo-5-(2,4-difluorophenoxy)benzoate

Example 324c was prepared according to the procedure used for thepreparation of Example 7b, substituting Example 324b for Example 7a toafford the title compound.

Example 324d 4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzoicacid

Example 324d was prepared according to the procedure used for thepreparation of Example 7c, substituting Example 324c for Example 7b toafford the title compound.

Example 324e4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzamide

Oxalyl chloride (0.046 mL, 0.54 mmol) was added dropwise to a suspensionof Example 324d (214 mg, 0.49 mmol) and dichloromethane (2.2 mL). 1 Dropdimethylformamide was added and the reaction mixture was stirred atambient temperature for 2 hours. The solvent was evaporated and theresidue was dried (in-vacuo). The resulting acid chloride was suspendedin tetrahydrofuran (1.0 mL) and was cooled to 0° C. as ammoniumhydroxide (0.65 mL, 4.7 mmol) was added dropwise. The reaction mixturewas stirred at ambient temperature for 2 hours. Ethyl acetate was addedand the solution was washed with water, saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 1-8% methanol/dichloromethane gradient) to afford the titlecompound (176 mg, 82% yield).

Example 324fN-(5-bromo-2-cyano-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide

To a suspension of Example 324e (230 mg, 0.53 mmol) and dioxane (1.5 mL)was added pyridine (0.14 mL, 1.7 mmol) followed by 2,2,2-trifluoroaceticanhydride (0.14 mL, 0.99 mmol). The reaction mixture was stirred atambient temperature for 1 hour. Water was added and the solution wasextracted with ethyl acetate. The organic layer was washed with water,saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 5-40% ethyl acetate/heptane gradient) toafford the title compound (135 mg, 61% yield).

Example 324gN-(2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide

Example 324g was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 324f for Example 6b toafford the title compound.

Example 324hN-(2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide

Example 324h was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 324g for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 1.32 (t,J=7.12 Hz, 3H) 3.20 (q, J=7.46, 5.76 Hz, 2H) 3.54-3.57 (m, 3H) 6.32 (t,J=2.71, 2.03 Hz, 1H) 7.03-7.11 (m, 1H) 7.24-7.32 (m, 1H) 7.32 (t, J=2.71Hz, 1H) 7.37 (s, 1H) 7.38-7.48 (m, 1H) 7.46 (s, 1H) 7.59 (s, 1H) 10.07(s, 1H) 12.13 (brs, 1H). MS (ESI+) m/z 485 [M+H]⁺.

Example 325 tert-butyl4-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

Example 325 was prepared according to the procedure used for thepreparation of Example 315, substituting tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylatefor pyridin-3-ylboronic acid to afford the title compound. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.93 (s, 1H), 7.40-7.34 (m, 2H), 7.27-7.22 (m, 2H),7.04 (d, J=9.0 Hz, 1H), 6.13-6.09 (m, 1H), 6.07 (s, 1H), 3.97 (s, 2H),3.83 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.52 (dd, J=9.1, 3.4 Hz, 2H), 2.45(s, 2H), 1.42 (d, J=5.3 Hz, 9H), 1.06-0.97 (m, 1H), 0.46-0.38 (m, 2H),0.26-0.17 (m, 2H). MS (ESI+) m/z 476.2 (M+H)⁺.

Example 3264-[5-(6-aminopyridin-3-yl)-2-(cyclopropylmethoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 326 was prepared according to the procedure used for thepreparation of Example 315, substituting5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine forpyridin-3-ylboronic acid to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.93 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.6,2.5 Hz, 1H), 7.49 (dd, J=6.3, 2.4 Hz, 2H), 7.30 (s, 1H), 7.25 (t, J=2.7Hz, 1H), 7.14-7.07 (m, 1H), 6.49 (t, J=7.5 Hz, 1H), 6.16 (t, J=2.4 Hz,1H), 5.94 (s, 2H), 3.86 (d, J=6.7 Hz, 2H), 3.57 (s, 3H), 1.14-1.00 (m,1H), 0.51-0.38 (m, 2H), 0.27-0.14 (m, 2H). MS (ESI+) m/z 387.2 (M+H)⁺.

Example 3274-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 327a ethyl1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 327a was prepared according to the procedure used for thepreparation of Example 6a, substituting Example 70e for Example 1e, toprovide the title compound.

Example 327b ethyl1-benzyl-4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 327b was prepared according to the procedure used for thepreparation of Example 138a, substituting Example 327a for Example 6a,and Example 168b for 2-bromo-1-fluoro-4-(methylsulfonyl)benzene,respectively, to provide the title compound.

Example 327c ethyl4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 327c was prepared according to the procedure used for thepreparation of Example 70j, substituting Example 327b for Example 70i,to provide the title compound.

Example 327d4-(2-((2,2-difluorocyclopropyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

To the solution of Example 327c (1 g, 2.460 mmol) and(2,2-difluorocyclopropyl) methanol (0.532 g, 4.92 mmol) indimethylsulfoxide (10 mL) was added cesium carbonate (1.203 g, 3.69mmol). The reaction mixture was sealed in a microwave tube and heated at110° C. for 5 days. During the 5 days, three additional batches of(2,2-difluorocyclopropyl)methanol (0.532 g, 4.92 mmol) were added intothe reaction mixture. The reaction mixture was poured into ethyl acetate(150 mL) and water (150 mL). The aqueous layer was extracted with ethylacetate (100 mL×2). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated to give thecorresponding ethyl ester (1.2 g, 1.869 mmol, 76% yield). The aqueouslayer was adjusted pH to about 3 with 1N HCl and the resulting solid wasfiltered and dried to give the title compound (0.30 g, 0.64 mmol).

Example 327e4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

To a solution of Example 327d (0.070 g, 0.15 mmol) in anhydrousdichloromethane (5 mL) were added oxalyl chloride (0.026 mL, 0.300 mmol)and dimethylformamide (0.581 μl, 7.50 μmol). The reaction mixture wasstirred at ambient temperature for 2 hours and then evaporated. Theresidue was dissolved in dichloromethane (5 mL) and treated with2,2,2-trifluoroethylamine (0.048 mL, 0.600 mmol) and the mixture wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between water (15 mL) and ethyl acetate (25 mL). The aqueouslayer was extracted with additional ethyl acetate (15 mL) twice. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by reverse phaseHPLC (C18, mobile phase A:water (10 mM NH₄HCO₃); B: acetonitrile,Gradient 25-60% B in A) to give the title compound (70 mg, 85%). ¹H NMR(400 MHz, CD₃OD) δ ppm 7.96-7.90 (m, 2H), 7.66-7.25 (m, 2H), 6.92 (s,1H), 4.29 (t, J=7.5 Hz, 1H), 4.16 (t, J=9.2 Hz, 1H), 4.05 (tt, J=9.2,4.5 Hz, 2H), 3.72 (s, 3H), 3.22 (q, J=7.4 Hz, 2H), 2.00 (td, J=12.0, 7.3Hz, 1H), 1.58-1.46 (m, 1H), 1.32-1.25 (m, 4H). MS (ESI+) m/z 548.1(M+H)⁺.

Example 3284-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 328a 1-((methylsulfonyl)methyl)-4-nitrobenzene

To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol) inN,N-dimethylformamide (25 mL) was added sodium methanesulfinate (7.10 g,69.6 mmol). The reaction mixture was stirred at 65° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and diluted withwater. The resulting suspension was stirred for 10 minutes and filteredthrough a medium frit to provide the title compound.

Example 328b 4-((methylsulfonyl)methyl)aniline

Example 328a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL) were addedto 5% Pd/C, wet (1.6 g, 0.376 mmol) in a 50 mL pressure bottle andstirred for 2 hours at 30 psi and 50° C. The mixture was filteredthrough a nylon membrane and washed with a small amount oftetrahydrofuran and methanol. The solvent was evaporated to provide thetitle compound.

Example 328c 2-iodo-4-((methylsulfonyl)methyl)aniline

To a solution of Example 328b (3.80 g, 20.5 mmol) inN,N-dimethylformamide (103 mL) was added N-iodosuccinimide (5.08 g,22.56 mmol). The reaction mixture was stirred at ambient temperature for1 hour. The reaction mixture was quenched with 150 mL 10% aqueous sodiumthiosulfate and 100 mL saturated aqueous sodium bicarbonate. Thereaction mixture was extracted with ethyl acetate. The combined organiclayers were washed with saturated aqueous sodium chloride andconcentrated. Water was added, and the resulting suspension was stirredat ambient temperature 10 minutes. The suspension was filtered, and thesolids collected was rinsed with water, and dried overnight to providethe title compound.

Example 328dN-(cyclopropylmethyl)-2-iodo-4-((methylsulfonyl)methyl)aniline

Example 328c (0.200 g, 0.643 mmol) and cyclopropanecarbaldehyde (0.062mL, 0.836 mmol) were suspended in dichloromethane (3.21 mL) and methanol(3.21 mL). Acetic acid (0.368 mL, 6.43 mmol) was added. The reactionmixture was heated at 50° C. for 30 minutes and then cooled to ambienttemperature. Polymer supported cyanoborohydride (0.817 g, 1.928 mmol)was added. The reaction mixture was stirred at ambient temperatureovernight. Cyclopropanecarbaldehyde (0.062 mL, 0.836 mmol) was added,and the reaction mixture was stirred at ambient temperature for 2 hours.The reaction mixture was filtered, thoroughly rinsed withdichloromethane, and concentrated. The residue was purified by flashchromatography (silica gel, 20-100% ethyl acetate/heptane gradient) toprovide the title compound.

Example 328e4-(2-((cyclopropylmethyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 328e was prepared according to the procedure used for thepreparation of Example 4a, substituting Example 328d for Example 7c toprovide the title compound.

Example 328f4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 328f was prepared according to the procedure used for thepreparation of Example 4b, substituting Example 328e for Example 4a toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.08 (bs,1H), 7.29 (t, J=2.3 Hz, 1H), 7.21 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (s, 1H),7.12 (d, J=2.1 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H),4.67 (t, J=5.7 Hz, 1H), 4.30 (bs, 2H), 3.55 (s, 3H), 2.96 (t, J=6.1 Hz,2H), 2.86 (s, 3H), 1.05-0.92 (m, 1H), 0.41-0.29 (m, 2H), 0.19-0.10 (m,2H). MS (ESI+) m/z 386.0 (M+H)⁺

Example 3294-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 329a 2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline

Example 329a was prepared according to the procedure used for thepreparation of Example 147a, substituting cyclopropylmethanamine forcyclohexanamine to provide the title compound.

Example 329b4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 329b was prepared according to the procedure used for thepreparation of Example 7d, substituting the product of Example 329a forthe product of Example 7c and stirring at 100° C. for 30 minutes, toprovide the title compound.

Example 329c4-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 329c was prepared according to the procedure used for thepreparation of Example 4 (Method B), substituting the product of Example329b for the product of Example 7d, and purified by Preparative HPLC(C18, 10-100% acetonitrile in 0.1% TFA/water) to provide the TFA salt ofthe title compound. 1H NMR (300 MHz, DMSO-d₆) □ ppm 12.12 (bds, 1H),7.67 (dd, J=2.4, 8.8 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.29 (t, J=3.1 Hz,1H), 7.26 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.02 (t, J=2.2 Hz, 1H), 5.45(m, 1H), 3.56 (s, 3H), 3.10 (m, 2H), 3.04 (m, 2H), 1.01 (m, 1H), 0.37(m, 2H), 0.16 (m, 2H). MS (ESI+) m/z 372.1 (M+H)⁺.

Example 3304-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 330a4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 168b (0.935 g, 3.50 mmol), Example 6a (1.5 g, 3.5mmol), tetrakis(triphenylphosphine)palladium(0) (0.202 g, 0.175 mmol)and cesium fluoride (1.596 g, 10.51 mmol) in 12 mL dimethoxyethane and 4mL methanol was heated at 120° C. under microwave conditions for 40minutes. The mixture was concentrated and the residue was absorbed onsilica gel and purified by flash chromatography (SiO₂, 0-10%methanol/dichloromethane gradient) to give the title compound (1.01 g,86% yield).

Example 330b4-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 330a (90 mg, 0.27 mmol) and pyrrolidine (668 μL,8.08 mmol) in 1 mL DMSO was heated at 160° C. under microwave conditionsfor 30 minutes. The product was purified by preparative HPLC (C18,10-80% CH₃CN/water (0.1% TFA)) to give the title compound (37 mg, 35.7%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.07 (s, 1H), 7.61 (dd, J=8.8,2.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.26 (t, J=2.8 Hz, 1H), 7.20 (s,1H), 6.95 (d, J=8.9 Hz, 1H), 5.99-5.94 (m, 1H), 3.56 (s, 3H), 3.16 (q,J=7.3 Hz, 2H), 3.06 (s, 4H), 1.69 (t, J=6.3 Hz, 4H), 1.10 (t, J=7.4 Hz,3H). MS (ESI+) m/z 386.1 (M+H)⁺.

Example 3314-[5-(ethylsulfonyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 331 was prepared according to the procedure used for thepreparation of Example 330b, substituting N-methylpiperazine forpyrrolidine, to afford the TFA salt of the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 12.12 (s, 1H), 9.57 (s, 1H), 7.80 (dd, J=8.5, 2.3Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.45 (s, 1H), 7.32 (dd, J=8.6, 5.7 Hz,2H), 6.17 (t, J=2.3 Hz, 1H), 3.60 (s, 3H), 3.49 (t, J=6.7 Hz, 2H), 3.28(q, J=7.4 Hz, 4H), 2.94 (t, J=11.8 Hz, 2H), 2.71 (s, 3H), 2.68-2.53 (m,2H), 1.13 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 415.2 (M+H)⁺.

Example 3324-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 332a4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 6a (1.71 g, 4.00 mmol), 2-bromo-4-(methylsulfonyl)aniline (1.00g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante(0.117 g, 0.400 mmol) and sodium carbonate (1.48 g, 14.0 mmol) werecombined and purged with argon for 15 minutes. A mixture of dioxane(21.3 mL) and water (5.3 mL) was purged with nitrogen for 15 minutes andtransferred to the reaction vessel. The reaction mixture was heated at60° C. for 3 hours, cooled to ambient temperature and diluted withwater. The resulting solid was filtered, washed with water and dried toafford the title compound (2.06 g, quantitative yield).

Example 332b4-(2-((4-fluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 332a (47.2 mg, 0.100 mmol), 1-bromo-4-fluorobenzene (17.5 mg,0.100 mmol), diacetoxypalladium (0.9 mg, 4 μmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (3.8mg, 8.0 μmol) and cesium carbonate (45.6 mg, 0.140 mmol) were combinedin a mixture of toluene (1.6 mL) and tert-butanol (0.4 mL). The reactionmixture was heated in a microwave reactor at 150° C. for 15 minutes. Thereaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedwith anhydrous sodium sulfate, treated with 3-mercaptopropylfunctionalized silica gel, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 2 to 4% methanol indichloromethane) to provide the title compound (30 mg, 53%).

Example 332c4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 332b (28 mg, 0.050 mmol), potassium hydroxide (41.7 mg, 0.743mmol) and cetyltrimethylammonium bromide (0.90 mg, 2.5 μmol) werecombined in a mixture of tetrahydrofuran (2 mL) and water (1 mL). Thereaction mixture was heated at 100° C. for 20 hours and then cooled toambient temperature. To this mixture was added water, and the pH wasadjusted to pH 7 by the addition of 1M HCl. The mixture was extractedwith ethyl acetate and the organic layer was washed with saturatedaqueous sodium chloride twice, dried with anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 2 to 4% methanol in dichloromethane) toprovide the title compound (13 mg, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm12.04 (s, 1H) 7.57-7.71 (m, 3H) 7.34 (s, 1H) 7.08-7.27 (m, 6H) 6.06 (t,J=2.20 Hz, 1H) 3.57 (s, 3H) 3.15 (s, 3H). MS (ESI+) m/z 412 (M+H)⁺.

Example 3334-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamideExample 333a 3-bromo-4-fluoro-N-(pyridin-3-ylmethyl)benzenesulfonamide

Example 333a was prepared according to the procedure used for thepreparation of Example 305a, substituting pyridin-3-ylmethanamine forindoline. The crude product was purified by crystallization from ethylacetate/ethyl ether to afford title compound

Example 333b3-bromo-4-(cyclopropylmethoxy)-N-(pyridin-3-ylmethyl)benzenesulfonamide

Example 333b was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol and substituting Example 333a for Example 2a toafford the title compound.

Example 333c4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide

Example 333c was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 333b for Example 6b toafford the title compound.

Example 333d4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide

Example 333d was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 333c for Example 6c, andpurified by Preparative HPLC (C18, 10-100% acetonitrile in 0.1%TFA/water) to provide the TFA salt of the title compound. ¹H NMR (300MHz, DMSO-d₆) □ ppm 12.03 (s, 1H) 8.55 (s, 2H) 8.17 (t, J=6.44 Hz, 1H)7.88 (d, J=7.80 Hz, 1H) 7.70-7.76 (m, 2H) 7.50 (dd, J=7.12, 4.75 Hz, 1H)7.27-7.32 (m, 2H) 7.20-7.26 (m, 1H) 6.10-6.16 (m, 1H) 4.11 (d, J=6.44Hz, 2H) 3.95 (d, J=6.78 Hz, 2H) 3.58 (s, 3H) 1.03-1.19 (m, 1H) 0.44-0.52(m, 2H) 0.24-0.31 (m, 2H). MS (ESI+) m/z 465.0 [M+H]⁺.

Example 3344-[4-(cyclopropylmethoxy)-3′-fluorobiphenyl-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 334a4-(5-bromo-2-(cyclopropylmethoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 334a was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 314a for Example 6b toafford the title compound.

Example 334b4-(4-(cyclopropylmethoxy)-3′-fluorobiphenyl-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 334b was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 334a for Example 6b andsubstituting (3-fluorophenyl)boronic acid for Example 6a to afford thetitle compound.

Example 334c4-(4-(cyclopropylmethoxy)-3′-fluorobiphenyl-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 334c was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 334b for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 0.22-0.28 (m,2H) 0.42-0.49 (m, 2H) 1.03-1.14 (m, 1H) 3.58 (s, 3H) 3.90 (d, J=6.78 Hz,2H) 6.17 (t, J=2.71, 2.03 Hz, 1H) 7.09-7.20 (m, 2H) 7.27 (t, J=3.05 Hz,1H) 7.34 (s, 1H) 7.42-7.55 (m, 3H) 7.62-7.69 (m, 2H) 11.98 (brs, 1H). MS(ESI+) m/z 389 [M+H]⁺.

Example 3354-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 335a4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 335a was prepared according to the procedure used for thepreparation of Example 4a, substituting Example 328c for Example 7c toprovide the title compound.

Example 335b4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

4-Bromofluorobenzene (0.027 mL, 0.25 mmol), Example 335a (0.100 g, 0.206mmol), palladium (II) acetate (1.849 mg, 8.24 μmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (7.85mg, 0.016 mmol), and cesium carbonate (0.094 g, 0.29 mmol) weresuspended in toluene (1.37 mL) and t-butanol (0.69 mL). The reactionmixture was heated at 150° C. for 30 minutes under microwave conditions.The reaction mixture was filtered through a 2.5 g Celite column andrinsed thoroughly with ethyl acetate. The filtrate was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and mercaptopropyl silica gel, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 0-4%methanol/dichloromethane gradient) to provide the title compound.

Example 335c4-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 335c was prepared according to the procedure used for thepreparation of Example 4b, substituting Example 335b for Example 4a toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.99 (bs,1H), 7.32 (d, J=2.1 Hz, 1H), 7.25 (dd, J=8.3, 2.0 Hz, 1H), 7.18-7.23 (m,4H), 6.97-7.07 (m, 4H), 6.06 (t, J=2.0 Hz, 1H), 4.40 (bs, 2H), 3.53 (s,3H), 2.91 (s, 3H). MS (ESI+) m/z 426.2 (M+H)⁺

Example 336[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetonitrile

A mixture of Example 314b (100 mg, 0.190 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (44.4 mg, 0.228mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II),complex with dichloromethane (1:1) (15.5 mg, 0.019 mmol), and potassiumfluoride (44.1 mg, 0.758 mmol) in dimethylsulfoxide (1.9 mL) and water(0.75 mL) was purged with nitrogen gas and heated under microwaveconditions at 130° C. at for 1.5 hours. The mixture was then treatedwith 1 mL 4N NaOH and stirred at ambient temperature for 2 hours. Thereaction mixture was partitioned between water and ethyl acetate, andthe aqueous layers was extracted with ethyl acetate. The combinedorganic phases were washed with water (2×), saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated and the residue was purified by flashchromatography (silica gel, 0-8% methanol/dichloromethane gradient) togive the title compound (30 mg, 48% yield). ¹H NMR (300 MHz, DMSO-d₆) δppm 12.00 (s, 1H), 12.00 (s, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.34-7.25 (m,4H), 7.30-7.25 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H),6.14 (dd, J=2.6, 2.2 Hz, 1H), 6.14 (dd, J=2.6, 2.2 Hz, 1H), 3.99 (s,2H), 3.99 (s, 2H), 3.84 (d, J=6.7 Hz, 2H), 3.84 (d, J=6.7 Hz, 2H), 3.56(s, 3H), 3.56 (s, 3H), 1.11-1.02 (m, 1H), 1.12-1.02 (m, 1H), 0.48-0.39(m, 2H), 0.49-0.35 (m, 2H), 0.31-0.18 (m, 2H), 0.26-0.19 (m, 2H). MS(ESI+) m/z 334.1 (M+H)⁺.

Example 337N-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamideExample 337a ethyl4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-1-benzyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 337a was prepared according to the procedure used for thepreparation of Example 138a, substituting Example 70e for2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for Example6a, respectively, to provide the title compound.

Example 337b ethyl1-benzyl-4-(2-(2,4-difluorophenoxy)-5-(N-(ethylsulfonyl)ethylsulfonamido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 337b was prepared according to the procedure used for thepreparation of Example 320f, substituting Example 337a for Example 320e,to provide the title compound.

Example 337c ethyl4-(2-(2,4-difluorophenoxy)-5-(N-(ethylsulfonyl)ethylsulfonamido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 337c was prepared according to the procedure used for thepreparation of Example 70j, substituting Example 337b for Example 70i,to provide the title compound.

Example 337d4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

Example 337d was prepared according to the procedure used for thepreparation of Example 70k, substituting Example 337c for Example 70j,to provide the title compound.

Example 337eN-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide

Example 337d (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL) was treatedwith 1.0 N borane (0.119 mL, 0.119 mmol). The reaction mixture washeated at 60° C. for 2 hours. The reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was extracted withadditional ethyl acetate twice. The combined organic layer were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by reversephase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to give thetitle product. (0.035 g, 60% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm11.81 (s, 1H), 9.78 (s, 1H), 7.33-7.39 (m, 2H), 7.28 (s, 1H), 7.20 (dd,J=8.7, 2.59 Hz, 1H), 6.97-7.08 (m, 2H), 6.91 (d, J=8.85 Hz, 1H), 6.15(d, J=2.14 Hz, 1H), 4.50 (s, 2H), 3.52 (s, 3H), 3.10 (q, J=7.32 Hz, 2H),1.23 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 490.2 (M+H)⁺.

Example 338N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamideExample 338a4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbonylchloride

Example 338a was prepared according to the procedure used for thepreparation of Example 13a, substituting Example 337d for Example 10, toprovide the title compound.

Example 338bN-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide

Example 338b was prepared according to the procedure used for thepreparation of Example 13b, substituting Example 338a for Example 13a,and 1-methylpiperazine for ethylamine, respectively, to provide the TFAsalt of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.53 (s,1H), 10.14 (br s, 1H), 9.81 (s, 1H), 7.34-7.40 (m, 3H), 7.20 (dd,J=8.85, 2.75 Hz, 1H), 7.06-7.12 (m, 1H), 6.98-7.04 (m, 1H), 6.93 (d,J=8.54 Hz, 1H), 6.53 (d, J=2.14 Hz, 1H), 3.55 (s, 3H), 3.02-3.43 (m,6H), 2.84 (s, 3H), 1.24 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 586.2 (M+H)⁺.

Example 339N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide

Example 339 was prepared according to the procedure used for thepreparation of Example 337e, substituting Example 338b for Example 337d,to provide the TFA salt of the title compound. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 12.01 (s, 1H), 9.80 (s, 1H), 7.34-7.39 (m, 2H), 7.31 (s, 1H), 7.19(dd, J=8.85, 2.75 Hz, 1H), 7.05-7.11 (m, 1H), 6.98-7.04 (m, 1H), 6.91(d, J=8.85 Hz, 1H), 6.19 (d, J=2.14 Hz, 1H), 3.75 (s, 2H), 3.11 (q,J=7.32 Hz, 2H), 2.95 (br s, 2H), 2.76 (s, 3H), 2.35 (br s, 2H), 1.24 (t,J=7.32 Hz, 3H). MS (ESI+) m/z 572.0 (M+H)⁺.

Example 3404-[2-(cyclopropylmethoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 325 (100 mg, 0.210 mmol) in 2 mL dichloromethane was treatedwith 1 mL trifluoroacetic acid. The mixture was stirred at ambienttemperature for 2 hours. The solvent was evaporated. The residue wastreated with saturated aqueous sodium carbonate solution and thenextracted with ethyl acetate (4×). The organic phase was dried overanhydrous magnesium sulfate, filtered, and concentrated to give thetitle compound (26 mg, 32.9% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.94 (s, 1H), 7.37-7.31 (m, 1H), 7.25 (dd, J=5.3, 3.0 Hz, 2H), 7.18 (d,J=2.2 Hz, 1H), 7.13 (dd, J=8.4, 2.3 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H),6.12 (m, 2H), 3.80 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.09 (d, J=12.1 Hz,2H), 2.73-2.53 (m, 2H), 1.76 (d, J=11.0 Hz, 1H), 1.55 (qd, J=12.4, 3.8Hz, 2H), 1.12-1.01 (m, 1H), 0.49-0.38 (m, 2H), 0.25-0.17 (m, 2H). MS((DCI+) m/z 376.5 (M+H)⁺.

Example 341N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide

To a 4 mL vial was added (azidocarbonyl) dipiperidine (ADDP) (25.9 mg,0.102 mmol) in anhydrous toluene. The vial was introduced into a dry boxand tributylphosphine (41.5 mg, 3 eq, 0.205 mmol) was added to the vial.This mixture was shaken until the solution turned clear. To thissolution was added a solution of 2-methoxyethanol in anhydroustetrahydrofuran (1.2 equivalents, 0.082 mmol, 6.24 mg). This mixture wasstirred for 10 minutes at ambient temperature. To this mixture was addeda solution of Example 36e (0.068 mmol, 31.4 mg) in anhydroustoluene/anhydrous tetrahydrofuran (1:1 v/v) (1 mL). The reaction mixturewas stirred at room temperature overnight in the dry box. The reactionmixture was concentrated to dryness and the residue purified by reversephase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to provide thetitle compound (4.24%, 1.5 mg). ¹H NMR (400 MHz, DMSO d₆/D₂O) δ ppm 7.49(d, J=2.75 Hz, 1H), 7.38-7.43 (m, 1H), 7.37 (d, J=2.75 Hz, 1H),7.35-7.36 (m, 1H), 7.34 (d, J=2.75 Hz, 1H), 7.22-7.27 (m, 1H), 7.05-7.11(m, 1H), 6.87 (d, J=8.54 Hz, 1H), 6.30 (d, J=2.75 Hz, 1H), 3.78-3.81 (m,2H), 3.57 (s, 3H), 3.37 (t, J=5.65 Hz, 2H), 3.20 (s, 3H), 3.16 (t,J=7.32 Hz, 2H), 1.26 (t, J=7.48 Hz, 3H). ESI⁺ m/z=518.0 (M+H)⁺.

Example 342N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(pyridin-2-ylmethyl)ethanesulfonamide

Example 342 was prepared according to the procedure used for thepreparation of Example 341, substituting pyridin-2-ylmethanol for2-methoxyethanol, to provide the TFA salt of the title compound. ¹H NMR(400 MHz, DMSO d₆/D₂O) δ ppm 8.60 (d, J=4.58 Hz, 1H), 8.07 (t, J=7.78Hz, 1H), 7.70 (d, J=7.93 Hz, 1H), 7.56 (d, J=2.44 Hz, 1H), 7.53 (dd,J=7.02, 5.80 Hz, 1H), 7.45 (dd, J=8.85, 2.75 Hz, 1H), 7.35-7.41 (m, 1H),7.33 (d, J=2.75 Hz, 1H), 7.29 (s, 1H), 7.17-7.23 (m, 1H), 7.03-7.09 (m,1H), 6.81 (d, J=8.85 Hz, 1H), 6.17 (d, J=2.75 Hz, 1H), 5.10 (s, 2H),3.56 (s, 3H), 3.33 (q, J=7.43 Hz, 2H), 1.31 (t, J=7.32 Hz, 3H). ESI⁺m/z=551.0 (M+H)⁺.

Example 343N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 343 was prepared according to the procedure used for thepreparation of Example 341, substituting cyclopropylmethanol for2-methoxyethanol, to provide the title compound. ¹H NMR (400 MHz, DMSOd₆/D₂O) δ ppm 7.51 (d, J=2.44 Hz, 1H), 7.36-7.42 (m, 2H), 7.35 (s, 1H),7.34 (d, J=2.75 Hz, 1H), 7.20-7.27 (m, 1H), 7.04-7.10 (m, 1H), 6.88 (d,J=8.85 Hz, 1H), 6.29 (d, J=2.75 Hz, 1H), 3.57 (s, 3H), 3.52 (d, J=7.02Hz, 2H), 3.12-3.18 (m, 2H), 1.26 (t, J=7.32 Hz, 3H), 0.83-0.93 (m, 1H),0.40-0.45 (m, 2H), 0.08-0.13 (m, 2H). ESI⁺ m/z=514.0 (M+H)⁺.

Example 344N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]ethanesulfonamide

Example 344 was prepared according to the procedure used for thepreparation of Example 341, substituting1-(2-hydroxyethyl)pyrrolidin-2-one for 2-methoxyethanol, to provide thetitle compound. ¹H NMR (400 MHz, DMSO d₆/D₂O) δ ppm 7.50 (d, J=2.44 Hz,1H), 7.38-7.43 (m, 2H), 7.37 (s, 1H), 7.33 (d, J=2.75 Hz, 1H), 7.22-7.28(m, 1H), 7.05-7.11 (m, 1H), 6.84 (d, J=8.54 Hz, 1H), 6.34 (d, J=2.75 Hz,1H), 3.83 (t, J=5.65 Hz, 2H), 3.58 (s, 3H), 3.27-3.32 (m, 4H), 3.14 (q,J=7.32 Hz, 2H), 2.11 (t, J=8.09 Hz, 2H), 1.74-1.82 (m, 2H), 1.25 (t,J=7.32 Hz, 3H). ESI⁺ m/z=571.1 (M+H)⁺.

Example 345N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonamide

Example 345 was prepared according to the procedure used for thepreparation of Example 341, substituting (tetrahydrofuran-2-yl)methanolfor 2-methoxyethanol, to provide the title compound. ¹H NMR (400 MHz,DMSO d₆/D₂O) δ ppm 7.51 (d, J=2.75 Hz, 1H), 7.37-7.43 (m, 2H), 7.36 (s,1H), 7.34 (d, J=2.75 Hz, 1H), 7.21-7.27 (m, 1H), 7.04-7.11 (m, 1H), 6.86(d, J=8.85 Hz, 1H), 6.31 (d, J=2.75 Hz, 1H), 3.78-3.84 (m, 1H),3.58-3.70 (m, 4H), 3.57 (s, 3H), 3.13-3.19 (m, 2H), 1.73-1.93 (m, 3H),1.51-1.59 (m, 1H), 1.25 (t, J=7.32 Hz, 3H). ESI⁺ m/z=544.0 (M+H)⁺.

Example 346N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide

Example 346 was prepared according to the procedure used for thepreparation of Example 341, substituting 3,3,3-trifluoropropan-1-ol for2-methoxyethanol, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm 7.54 (d, J=2.75 Hz, 1H), 7.31-7.44 (m, 4H), 7.23-7.30(m, 1H), 7.05-7.11 (m, 1H), 6.89 (d, J=8.54 Hz, 1H), 6.31 (d, J=2.75 Hz,1H), 3.93-3.98 (m, 2H), 3.57 (s, 3H), 3.18 (q, J=7.32 Hz, 2H), 2.41-2.51(m, 2H), 1.25 (t, J=7.32 Hz, 3H). ESI⁺ m/z=556.0 (M+H)⁺.

Example 3474-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamideExample 347a 3-bromo-4-fluoro-N-(4-fluorophenyl)benzenesulfonamide

Example 347a was prepared according to the procedure used for thepreparation of Example 305a, substituting 4-fluoroaniline for indoline.The crude product was purified by flash chromatography (silica gel, 10%ethyl acetate in heptane) to afford title compound

Example 347b3-bromo-4-(cyclopropylmethoxy)-N-(4-fluorophenyl)benzenesulfonamide

Example 347b was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol and substituting Example 347a for Example 2a toafford the title compound.

Example 347c4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

Example 347c was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 347b for Example 6b toafford the title compound.

Example 347d4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide

Example 347d was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 347c for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 12.04 (s, 1H)10.07 (s, 1H) 7.60-7.68 (m, 2H) 7.23-7.31 (m, 2H) 7.20 (d, J=9.16 Hz,1H) 7.12 (d, J=6.78 Hz, 4H) 5.88-5.95 (m, 1H) 3.92 (d, J=6.78 Hz, 2H)3.55 (s, 3H) 1.02-1.17 (m, 1H) 0.43-0.50 (m, 2H) 0.22-0.30 (m, 2H). MS(ESI+) m/z 468.1 [M+H]⁺.

Example 3484-[2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 348a4-(2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 348a was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 334a for Example 6b andsubstituting (6-fluoropyridin-3-yl)boronic acid for Example 6a to affordthe title compound.

Example 348b4-(2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 348b was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 348a for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 0.21-0.28 (m,2H) 0.41-0.49 (m, 2H) 1.03-1.15 (m, 1H) 3.57 (s, 3H) 3.91 (d, J=6.78 Hz,2H) 6.17 (t, J=2.71, 2.03 Hz, 1H) 7.17-7.28 (m, 3H) 733 (s, 1H)7.63-7.69 (m, 2H) 8.23-8.32 (m, 1H) 8.54 (d, J=2.37 Hz, 1H) 11.95 (brs,1H). MS (ESI+) m/z 390 [M+H]⁺.

Example 349N-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 349a 4-bromo-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 1e (7 g, 18.36 mmol) and lithium hydroxidemonohydrate (3.08 g, 73.4 mmol) in tetrahydrofuran (50 mL) and water (20mL) was heated at 80° C. overnight. After cooling to ambienttemperature, the reaction mixture was poured into 300 mL of water. Theresulting solid was collected by vacuum filtration to give the titlecompound (3.92 g, 17.26 mmol, 94% yield).

Example 349b4-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 349a (3.92 g, 17.26 mmol) in tetrahydrofuran (100 mL) wastreated with 60% sodium hydride (1.036 g, 25.9 mmol). The reaction wasstirred at ambient temperature for 10 minutes. To this solution wasadded (2-(chloromethoxy)ethyl)trimethylsilane (4.58 mL, 25.9 mmol). Thereaction mixture was stirred overnight. The resulting solid was filteredoff, and the filtrate was concentrated. The residue was purified byflash chromatography (silica gel, 20% ethyl acetate in helptanes) togive the title compound (5.84 g, 95% yield).

Example 349c4-bromo-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde

Example 349b (3.92 g, 17.3 mmol) in dimethylformamide (15 mL) wastreated with phosphorus oxychloride (9.66 mL, 104 mmol) dropwise at 0°C. After the addition was complete, the solution was heated at 80° C.for 6 hours. After cooling to ambient temperature, the reaction mixturewas partitioned between water and ethyl acetate. The organic layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 50-100% ethylacetate/heptanes) to give the title compound (1.35 g, 20.3% yield).

Example 349d4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde

Example 349d was prepared according to the procedure used for thepreparation of Example 138a, substituting Example 349c for2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for Example6a, respectively, to provide the title compound. After aqueous workup,the crude product was used for the next reaction without purification.

Example 349eN-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

A mixture of Example 349d (0.5 g, 0.951 mmol), ethanesulfonyl chloride(0.226 mL, 2.38 mmol) and triethylamine (0.817 mL, 5.71 mmol) indichloromethane (10 mL) was stirred at ambient temperature for 2 hours.The solvent was evaporated under reduced pressure, and the residue wastreated with dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Thereaction mixture was stirred at ambient temperature for 3 hours. Thesolvent was removed under reduced pressure, and the residue was treatedwith dixoane (10 mL) and 2.0 N NaOH (5 mL). The reaction mixture washeated at 90° C. for 2 hours. After cooling to ambient temperature, thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, ethyl acetate) to give the title compound (0.42 g, 0.862 mmol, 91%yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.07 (s, 1H), 9.78 (s, 1H),9.40, (s, 1H), 7.99 (d, J=3.36 Hz, 1H), 7.38 (s, 1H), 7.23-7.31 (m, 3H),6.89-6.97 (m, 3H), 3.55 (s, 3H), 3.10 (q, J=7.32 Hz, 2H), 1.21 (t,J=7.32 Hz, 3H). MS (ESI+) m/z 488.0 (M+H)⁺.

Example 350N-{4-(2,4-difluorophenoxy)-3-[6-methyl-3-(morpholin-4-ylmethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide

A mixture of Example 349e (0.04 g, 0.082 mmol), morpholine (0.014 g,0.164 mmol), and sodium triacetoxyhydroborate (0.035 g, 0.164 mmol) in1,2-dichloroethane (2 mL) was stirred at ambient temperature overnight.The solvent was evaporated under reduced pressure, and the residue waspurified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1%TFA/water) to give the TFA salt of the title compound (0.035 g, 0.052mmol, 63.4% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.59 (s, 1H), 9.86(s, 1H), 9.58, (s, 1H), 7.56 (s, 1H), 7.26-7.38 (m, 4H), 7.00-7.09 (m,2H), 6.93 (d, J=8.85 Hz, 1H), 4.23-4.29 (m, 1H), 3.75-3.81 (m, 3H), 3.52(s, 3H), 3.16 (q, J=7.32 Hz, 2H), 2.37-2.71 (m 4H), 1.24 (t, J=7.32 Hz,3H). MS (ESI+) m/z 558.9 (M+H)⁺.

Example 351N-[4-(2,4-difluorophenoxy)-3-{6-methyl-3-[(4-methylpiperazin-1-yl)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide

Example 351 was prepared according to the procedure used for thepreparation of Example 350, substituting 1-methylpiperazine formorpholine, to provide the TFA salt of the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.11 (s, 1H), 9.86 (s, 1H), 9.58, (s, 1H),7.29-7.35 (m, 2H), 7.20-7.22 (m, 2H), 7.11 (s, 1H), 6.97-7.06 (m, 2H),6.91 (d, J=9.46 Hz, 1H), 3.85 (br s, 4H), 3.48 (s, 3H), 3.12-3.40 (m,4H), 2.69 (s, 3H), 1.25 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 571.9 (M+H)⁺.

Example 3524-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 352a 2-bromo-N-(cyclopropylmethyl)aniline

A solution of 2-bromoaniline (1.720 g, 10.00 mmol),cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid (2.86mL, 50.0 mmol) in dichloromethane (50 mL) was heated at 50° C. for 1hour. The solution was cooled in an ice bath and sodiumtriacetoxyborohydride (2.119 g, 10.00 mmol) was added. This mixture wasstirred for 2 hours while warming to ambient temperature and thenpartitioned between saturated sodium bicarbonate solution (100 mL) andethyl acetate (100 mL). The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel, 0-10% ethyl acetate in heptane)to provide the title compound (1.05 g, 93% yield).

Example 352b4-(2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 352b was prepared according to the procedure used for thepreparation of Example 4a, substituting Example 352a for Example 7c withthe exception that the reaction mixture was heated at 90° C. for 2.5hours and the material was purified by flash column chromatography(silica gel, 0-5% methanol in dichloromethane) to provide the titlecompound.

Example 352c4-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 352c was prepared according to the procedure used for thepreparation of Example 4b, substituting Example 352b for Example 4a withthe exception that the reaction was heated at 90° C. for 2.5 hours andthe material was purified by flash column chromatography (silica gel,0-5% methanol in dichloromethane) to provide the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 10.99 (s, 1H) 7.24-7.31 (m, 2H) 7.15 (dd, J=7.32,1.53 Hz, 1H) 6.97 (s, 1H) 6.70-6.78 (m, 2H) 6.20-6.25 (m, 1H) 3.99 (s,1H) 3.73 (s, 3H) 2.97 (d, J=6.41 Hz, 2H) 0.90-1.02 (m, 1H) 0.38-0.45 (m,2H) 0.09-0.15 (m, 2H). MS (ESI+) m/z 294.0 (M+H)⁺.

Example 3534′-(cyclopropylmethoxy)-3′-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)biphenyl-3-carbonitrileExample 353a4′-(cyclopropylmethoxy)-3′-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)biphenyl-3-carbonitrile

Example 353a was prepared according to the procedure used for thepreparation of Example 6c, substituting Example 334a for Example 6b andsubstituting (3-cyanophenyl)boronic acid for Example 6a to afford thetitle compound.

Example 353b4′-(cyclopropylmethoxy)-3′-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)biphenyl-3-carbonitrile

Example 353b was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 353a for Example 6c toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) □ ppm 0.21-0.28 (m,2H) 0.41-0.49 (m, 2H) 1.00-1.15 (m, 1H) 3.58 (s, 3H) 3.91 (d, J=6.78 Hz,2H) 6.17 (t, J=2.03 Hz, 1H) 7.20 (d, J=8.48 Hz, 1H) 7.26 (t, J=2.71 Hz,1H) 7.33 (s, 1H) 7.63 (t, J=7.80 Hz, 1H) 7.67-7.79 (m, 3H) 8.03 (d,J=8.14 Hz, 1H) 8.16 (t, J=1.70 Hz, 1H) 11.94 (brs, 1H). MS (ESI+) m/z396 [M+H]⁺.

Example 3544-{2-(cyclopropylmethoxy)-5-[(4-hydroxypiperidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 354a 1-(3-bromo-4-fluorophenylsulfonyl)piperidin-4-ol

Example 354a was prepared according to the procedure described for thepreparation of Example 310a, substituting piperidin-4-ol forN,N-dimethylpyrrolidin-3-amine to afford the title compound.

Example 354b1-(3-bromo-4-fluorophenylsulfonyl)-4-(tetrahydro-2H-pyran-2-yloxy)piperidine

3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0 OCsolution of Example 354a (0.51 g, 1.5 mmol), 4-methylbenzenesulfonicacid hydrate (0.59 g, 3.1 mmol), and dichloromethane (28 mL). Thereaction mixture was stirred at ambient temperature for 5 hours. Waterwas added and the mixture was extracted with dichloromethane. Theorganic layer was washed with water, saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography (silica gel,dichloromethane/gradient with methanol) to afford the title compound(420 mg, 65.9% yield).

Example 354c1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl)-4-(tetrahydro-2H-pyran-2-yloxy)piperidine

Example 354c was prepared according to the procedure used for thepreparation of Example 29a, substituting cyclopropylmethanol fortetrahydro-2H-pyran-4-ol and substituting Example 354b for Example 2a toafford the title compound.

Example 354d4-(2-(cyclopropylmethoxy)-5-(4-(tetrahydro-2H-pyran-2-yloxy)piperidin-1-ylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 354d was prepared according the to the procedure used for thepreparation of Example 6c, substituting Example 354c for Example 6b toafford the title compound.

Example 354e4-(2-(cyclopropylmethoxy)-5-(4-(tetrahydro-2H-pyran-2-yloxy)piperidin-1-ylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 354e was prepared according to the procedure used for thepreparation of Example 6d, substituting Example 354d for Example 6c toafford the title compound.

Example 354f4-(2-(cyclopropylmethoxy)-5-(4-hydroxypiperidin-1-ylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A solution of Example 354e (54 mg, 0.10 mmol), acetic acid (4 mL, 69.9mmol), tetrahydrofuran (2 mL) and water (1 mL) was stirred at 45° C. for2.5 hours. The reaction mixture was concentrated to dryness and theresidue was dried overnight (in-vacuo). The crude product was trituratedwith diethyl ether, filtered and dried (in-vacuo) to afford the titlecompound (30 mg, 66% yield). ¹H NMR (300 MHz, DMSO-d₆) □ ppm 0.25-0.31(m, 2H) 0.44-0.51 (m, 2H) 1.08-1.17 (m, 1H) 1.38-1.51 (m, 2H) 1.70-1.80(m, 2H) 2.70-2.80 (m, 2H) 3.10-3.18 (m, 2H) 3.51-3.56 (m, 1H) 3.57 (s,3H) 3.97 (d, J=6.78 Hz, 2H) 4.66 (d, J=4.07 Hz, 1H) 6.12 (t, J=2.71,2.03 Hz, 1H) 7.27-7.32 (m, 2H) 7.36 (s, 1H) 7.64-7.70 (m, 2H) 12.04(brs, 1H). MS (ESI+) m/z 458 [M+H]⁺.

Biological Examples Bromodomain Domain Binding Assay

A time-resolved fluorescence resonance energy transfer (TR-FRET) assaywas used to determine the affinities of compounds of the Examples listedin Table 1 for each bromodomain of human BRD4. His-tagged first (BD1:amino acids K57-E168) and second (BD2: amino acids E352-E168)bromodomains of human BRD4 were expressed and purified. AnAlexa647-labeled BET-inhibitor was used as the fluorescent probe in theassay.

Synthesis of Alexa647-Labeled Bromodomain Inhibitor Compound2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid

Methyl2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate(see e.g., WO 2006129623) (100.95 mg, 0.243 mmol was suspended in 1 mLmethanol to which was added a freshly prepared solution of lithiumhydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken atambient temperature for 3 hours. The methanol was evaporated and the pHadjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) andextracted four times with ethyl acetate. The combined ethyl acetatelayers were dried over magnesium sulfate and concentrated to afford2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)⁺] which was used directlyin the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate)

2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 0.213 mmol) was combined with2,2′-(ethane-1,2-diylbis(oxy))diethanamine (Sigma-Aldrich, 0.315 mg,2.13 mmol) were combined in 5 mL anhydrous dimethylformamide.(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg, 0.638mmol) was added and the reaction shaken at ambient temperature for 16hours. The reaction mixture was diluted to 6 mL withdimethylsulfoxide:water (9:1, v:v) and purified in two injections withtime collection Waters Deltapak C18 200×25 mm column eluted with agradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile.The fractions containing the two purified products were lyophilized toaffordN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z=531.1[(M+H)+]; 529.1 [(M−H)-] and(S,Z)—N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)bis(2,2,2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS m/z=913.2 [(M+H)+];911.0 [(M−H)⁻].

N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was combined withAlexa Fluor® 647 carboxylic Acid, succinimidyl ester (Life Technologies,Grand Island, N.Y.; 3 mg, 0.0024 mmol) were combined in 1 mL anhydrousdimethylsulfoxide containing diisopropylethylamine (1% v/v) and shakenat ambient temperature for 16 hours. The reaction was diluted to 3 mLwith dimethylsulfoxide:water (9:1, v:v) and purified in one injectionwith time collection Waters Deltapak C18 200×25 mm column eluted with agradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile.The fractions containing the purified product were lyophilized to affordN-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)(1.8 mg); MALDI-MS m/z=1371.1, 1373.1 [(M+H)⁺] as a dark blue powder.

Assay

Compound dilution series were prepared in DMSO via a 3-fold serialdilution from 2.5 mM to 42 nM. Compounds were then diluted 6:100 inassay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mMEthylenediaminetetraacetic acid disodium salt dihydrate, 0.01% TritonX-100, 1 mM DL-Dithiothreitol) to yield 3× working solutions. Sixmicroliters (□L) of the working solution was then transferred to white,low-volume assay plates (Costar #3673). A 1.5× assay mixture containingHis-tagged bromodomain, Europium-conjugated anti-His antibody(Invitrogen PV5596) and the Alexa-647-conjugated probe molecule was alsoprepared. Twelve □L of this solution were added to the assay plate toreach a final volume of 18 □L. The final concentration of 1× assaybuffer contains 2% DMSO, 50 □M-0.85 nM compound, 8 nM His-taggedbromodomain, 1 nM Europium-conjugated anti-His-tag antibody and 100 nMor 30 nM probe (for BDI or BDII, respectively). After a one-hourincubation at room temperature, TR-FRET ratios were determined using anEnvision multilabel plate reader (Ex 340, Em 495/520).

TR-FRET data were normalized to the means of 24 no-compound controls(“high”) and 8 controls containing 1 μM un-labeled probe (“low”).Percent inhibition was plotted as a function of compound concentrationand the data were fit with the 4 parameter logistic equation to obtainIC₅₀s. Inhibition constants (K_(i)) were calculated from the IC₅₀s,probe K_(d) and probe concentration. Typical Z′ values were between 0.65and 0.75. The minimum significant ratio was determined to evaluate assayreproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261).The MSR was determined to be 2.03 for BDI and 1.93 for BDII, and amoving MSR (last six run MSR overtime) for both BDI and BDII wastypically <3. The K_(i) values are reported in Table 1.

MX-1 Cell Line Proliferation Assay

The impact of compounds of the Examples on cancer cell proliferation wasdetermined using the breast cancer cell line MX-1 (ATCC) in a 3-dayproliferation assay. MX-1 cells were maintained in RPMI 1640 medium(Sigma) supplemented with 10% FBS (Fetal Bovine Serum) at 37 C° and anatmosphere of 5% CO₂. For compound testing, MX-1 cells were plated in96-well black bottom plates at a density of 5000 cells/well in 90 μL ofculture media and incubated at 370 overnight to allow cell adhesion andspreading. Compound dilution series were prepared in DMSO via a 3-foldserial dilution from 3 mM to 0.1 □M. The DMSO dilution series were thendiluted 1:100 in phosphate buffered saline, and 10 □L of the resultedsolution were added to the appropriate wells of the MX-1 cell plate. Thefinal compound concentrations in the wells were 3, 1, 0.3, 0.1, 0.03,0.01, 0.003, 0.001, 0.0003 and 0.0001 DM. After the addition ofcompounds, the cells were incubated for 72 more hours and the amounts ofviable cells were determined using the Cell Titer Glo assay kit(Promega) according to manufacturer suggested protocol. Luminescencereadings from the Cell Titer Glo assay were normalized to the DMSOtreated cells and analyzed using the GraphPad Prism software withsigmoidal curve fitting to obtain EC₅₀s. The minimum significant ratio(MSR) was determined to evaluate assay reproducibility (Eastwood et al.,(2006) J Biomol Screen, 11: 253-261). The overall MSR was determined tobe 2.1 and a moving MSR (last six run MSR overtime) has been <2.

Proliferation Panel Assay

The compounds of Examples 4 and 78 were tested for their impact onproliferation of a panel of cancer cell lines types (with specific cellline tested) as set out in (Table 2). Cells were plated in 96-wellplates at 1500 cells/well in the appropriate culture media without testcompound and incubated overnight at 37° C. and an atmosphere of 5% CO₂.Series dilution of compounds were prepared and added to the wells as inthe MX-1 proliferation assay. After the addition of compounds, cellswere incubated for another 3 days at 37° C. and an atmosphere of 5% CO₂.The amounts of viable cells were determined using the Cell Titer Gloassay kit (Promega) according to manufacturer suggested protocol. Cellproliferation data were analyzed as described above in the MX-1proliferation assay to obtain the EC₅₀ for the compounds of Examples 4and 78 and reported in Table 2.

TABLE 1 TR-FRET Binding TR-FRET Binding Cellular Ki: BRD4 Ki: BRD4proliferation: Compound (BDI_K57-E168) (BDII_E352-M457) EC₅₀ of Ex. No.(μM) (μM) (μM) 1 0.136* 0.0410* 0.137 2 0.529* 0.178* 0.860 3 0.06460.0736 0.185 4 0.0014* 0.0020* 0.0164 5 0.0150 0.0064 0.0310 6 0.00530.0058 0.0460 7 0.119 0.0773 >3.0 8 0.0026 0.0039 0.0244* 9 0.01800.0101 0.113* 10 0.0154 0.0086 >3.0 11 0.0018 0.0024 0.0342 12 1.84.33 >3.0 13 0.0037 0.0034 0.128 14 0.0055 0.0123 0.170 15 0.0042 0.00750.140 16 0.0043 0.0053 0.0946 17 0.0171* 0.0322* 0.283 18 0.0102*0.0103* 0.209 19 0.0074 0.0042 0.123 20 0.0109 0.00068 0.190 21 0.000390.00025 0.0139* 22 0.0022 0.0010 0.0652 23 0.0012 0.00075 0.0459 240.0025 0.0021 0.0126 25 0.0030 0.0036 0.0562 26 0.0021 0.0033 0.0171 270.0025* 0.0022* 0.0317 28 0.0017 0.0020 0.0239 29 0.0011 0.0067 0.071830 0.0177 0.0104 0.562 31 0.0018 0.0134 0.0398 32 0.0160 0.0075 0.083333 0.0026 0.0048 0.0417 34 0.0035 0.0021 0.0268 35 0.661 1.14 NA 360.0035* 0.0014* 0.0174* 37 0.0113 0.0108 0.0593 38 0.148 0.257 NA 390.112 0.124 NA 40 0.0145 0.0439 0.167 41 0.0028 0.00051 0.0298 42 0.05460.0934 >3.0 43 0.0017 0.0012 0.0169 44 0.286 0.236 0.828 45 0.01280.0190 0.233 46 0.0516 0.0169 0.588 47 0.235 0.205 1.1 48 0.0023 0.00330.0235 49 0.0017* 0.0015* 0.0196* 50 0.0215 0.0081 0.206* 51 0.00970.0161 0.101 52 0.0241 0.0260 0.309 53 0.0622 0.0054 0.0765 54 0.09510.0375 0.266 55 0.0555 0.0336 0.200 56 0.0122 0.0024 0.251 57 0.000880.0020 0.0138* 58 0.0021 0.0081 0.0451 59 0.00084 0.0016 0.0187* 600.00075 0.0066 0.0142* 61 >13.0 >22.2 NA 62 0.0030* 0.0019* 0.0079* 630.0180 0.0427 0.105 64 0.0531* 0.0633* 0.773 65 0.0116* 0.0049* 0.025566 0.00074 0.0034 0.0332 67 0.0561* 0.0938* 0.341 68 1.7 2.55 5.9 690.0390 0.0123 0.140 70 0.0118 0.0468 >3.0 71 0.00081* 0.0012* 0.0175* 720.0015* 0.0011* 0.0457* 73 0.00098 0.00050 0.0207 74 0.0961 0.101 0.27575 0.137 0.0594 0.478 76 0.0658 0.0297 0.290 77 0.0124 0.0157 >3.0 780.0025 0.0018 0.400 79 0.0062 0.0018 0.887 80 0.0091 0.0061 0.0620 810.0095 0.00099 0.103 82 0.519 0.183 0.767 83 0.0209 0.0422 0.424 840.00167 0.00065 0.231 85 0.0064 0.0017 0.0520 86 0.0043 0.0024 0.182 870.0056 0.0067 0.0534 88 0.635 0.236 >3.0 89 0.0016 0.0021 0.0252* 900.0040 0.0068 0.0168 91 0.0122 0.0874 0.240 92 0.0025 0.0253 0.0840 930.0076 0.0322 0.120 94 0.0162 0.0100 0.110 95 0.0087 0.0011 0.0560 960.00063 0.0011 0.0160 97 0.0023 0.0028 0.0140 98 0.0065 0.0027 0.0529 990.0035 0.0247 0.0977 100 0.0014 0.0027 0.107 101 0.0012 0.0043 0.0112102 0.0034 0.0242 0.0615 103 0.0019 0.0038 0.0338 104 0.0044 0.01790.0653 105 0.00052 0.0015 0.0160 106 0.0013 0.0109 0.0468 107 0.000500.00087 0.0310 108 0.0014 0.0053 0.0380 109 0.00072 0.0034 0.0320 1100.0031 0.0051 0.0324 111 0.0087 0.0103 0.199 112 0.0169 0.0206 0.240 1130.0474 0.381 >3.0 114 0.136 0.121 >3.0 115 0.0671 0.0269 0.0550 1160.105 0.0891 NA 117 2.3 0.486 NA 118 NA NA NA 119 0.0444 0.0225 NA 1200.190 0.304 NA 121 0.0155 0.0334 0.251 122 NA NA NA 123 0.0271 0.03610.118 124 0.320 0.169 NA 125 0.215 0.274 NA 126 2.0 0.768 NA 127 NA NANA 128 0.0725 0.112 NA 129 0.0379 0.0456 0.118 130 0.183 0.174 NA 1310.0986 0.0600 NA 132 0.238 0.344 NA 133 NA NA NA 134 0.0435 0.00730.137* 135 0.274 0.0774 NA 136 0.234 0.295 NA 137 0.0687 0.0089 0.303*138 0.0167 0.0095 0.0851 139 7.1 3.89 NA 140 3.6 1.58 NA 141 0.00540.0152 0.125 142 0.0065 0.0794 0.138 143 0.0223 0.107 0.370 144 0.01360.0178 0.0769 145 0.0027 0.0056 0.0264 146 0.0075 0.0019 0.0609 1470.0021 0.0011 0.0148 148 0.205 0.152 0.740 149 0.0115 0.0030 0.0297 1500.0097 0.0042 0.0665 151 0.0107 0.0081 0.0549 152 0.0246 0.0048 0.105153 0.0228 0.0082 0.0933 154 0.0208 0.0131 0.0655 155 0.0193 0.01480.117 156 0.0113 0.0209 0.114 157 0.0308 0.0218 0.150 158 0.0041*0.0097* 0.0243* 159 0.0370 0.0207 0.0624 160 0.0416 0.0065 0.119 1610.0204 0.0055 0.104 162 0.0111 0.0046 0.127 163 0.0857 0.0235 0.295 164NA NA NA 165 0.0050 0.0022 0.104 166 0.0109 0.0036 0.0482 167 0.00650.0122 0.0430 168 0.0054 0.0013 0.0277 169 0.00088* 0.00086* 0.0053 1700.0228 0.0940 0.332 171 0.0138 0.0103 NA 172 0.0133 0.0059 NA 173 0.01570.0066 NA 174 0.0192 0.0143 NA 175 0.0258 0.0178 NA 176 0.0213 0.0060 NA177 0.0113 0.0044 0.0535 178 0.0105 0.0032 0.0362 179 0.0225 0.0165 NA180 0.0179 0.0071 0.115 181 0.0305 0.0224 NA 182 0.0190 0.0097 NA 1830.0412 0.0198 NA 184 0.0166 0.0045 0.0788 185 0.0345 0.0122 NA 1860.0101 0.0033 0.0484 187 0.0248 0.0082 NA 188 0.0294 0.0180 NA 1890.0304 0.0230 NA 190 0.0346 0.0181 NA 191 0.0178 0.0088 NA 192 0.05130.0096 NA 193 0.0704 0.0136 NA 194 0.0289 0.0191 NA 195 5.5 1.02 NA 1969.5 0.479 NA 197 0.0015 0.00079 0.0117 198 0.0013 0.0016 0.0093* 1990.0019 0.0035 NA 200 0.00086 0.0011 0.0113 201 0.0102 0.0407 0.135 2020.0017 0.0014 0.0228* 203 0.00069 0.00075 0.0047 204 0.0205 0.01020.0829 205 0.0062 0.0102 0.0391* 206 0.0116 0.0228 0.0777 207 0.00310.0018 0.0251* 208 0.0056 0.0060 0.0235 209 0.0046 0.0036 0.0368 2100.0045 0.0053 0.0367 211 0.0014 0.0021 0.0119 212 0.0018 0.0013 0.0073213 0.0032 0.0048 0.0287 214 0.0024 0.0017 0.0105 215 0.00083 0.000460.0019 216 0.0018 0.0018 0.0066 217 0.0033 0.0081 0.0342 218 0.06930.0689 NA 219 0.0036 0.0029 0.0177 220 0.0028 0.0012 0.0213 221 0.00660.0050 0.0061 222 0.225 0.969 NA 223 0.0024 0.0050 0.0133 224 0.00690.0070 0.0076 225 0.264 0.845 NA 226 0.141 0.438 >3.0 227 0.0739 0.2110.658 228 0.0390 0.108 >3.0 229 0.0343 0.0613 0.288 230 0.0026 0.00150.0236 231 0.0037 0.0067 0.0063 232 0.213 0.443 NA 233 0.0022* 0.0015*0.0069* 234 0.0030 0.0034 0.0159 235 0.0174 0.0070 0.0665 236 0.01450.0051 0.0250 237 0.0030 0.0035 0.0350 238 0.0011 0.00078 0.0033 2390.0028 0.0024 0.0101 240 0.0020 0.0028 0.0115 241 0.332 0.603 NA 2420.0365 0.0058 0.289 243 0.0115 0.0382 0.249 244 0.0232 0.0737 0.254 2450.0025 0.0037 0.0269 246 0.0180 0.0046 0.0975 247 1.1 3.00 NA 248 0.00190.0013 0.0264* 249 0.0015 0.00083 0.0144* 250 0.0015* 0.0015* 0.0180*251 0.0631 0.171 0.573 252 0.0101 0.0017 0.246 253 0.0204 0.0012 0.145254 0.0796 0.0087 0.0751 255 0.0105 0.154 0.265 256 0.0061 0.0840 0.405257 0.0588 0.0030 0.360 258 0.0059 0.0124 0.0765 259 0.0242 0.0203 0.123260 0.0010 0.0012 0.0063 261 0.0015 0.0016 0.0072 262 0.125 0.489 NA 2630.0088 0.0163 0.0769 264 0.0012 0.0012 0.0178 265 0.0090 0.0356 >3.0 2660.0215 0.0078 0.0564 267 0.0044 0.0042 0.0436 268 0.00076 0.00057 0.0062269 0.0124 0.0569 0.329 270 0.0487 0.0226 0.421 271 0.0029 0.0019 0.0213272 0.0102 0.0116 0.112 273 0.0012 0.0013 0.0090 274 0.0933 0.310 NA 2750.526 1.13 NA 276 0.0114 0.0171 0.149 277 0.0063 0.0143 0.0211 2780.0121 0.0112 0.135 279 0.0314 0.131 0.364 280 0.0192 0.0920 0.292 2810.0018 0.108 0.191 282 0.0173 0.0723 0.204 283 0.0189 0.0346 0.138 2840.0183 0.130 0.131 285 0.0108 0.0075 0.111 286 0.0121 0.0054 0.0746 2870.0089 0.0095 0.0195* 288 0.0719 0.0539 0.173 289 0.0124 0.310 >3.0 2900.0050 0.0019 0.0362 291 0.0329 0.0237 NA 292 0.0532 0.0558 0.366 2930.180 0.0193 0.381 294 0.0479 0.0217 0.332 295 0.0279 0.0307 0.223 2960.705 0.101 0.535 297 0.0142 0.0052 0.0186 298 0.0029 0.0031 0.0061 2990.0801 0.0050 0.0360 300 0.389 0.190 0.176 301 0.0179 0.0155 0.0421 3020.0058 0.0035 0.0169 303 0.0039 0.0071 0.335* 304 0.0090 0.0218 0.0323305 0.327 0.0257 0.110 306 0.0822 0.0639 0.0516 307 0.0024 0.0029 0.122308 0.0499 0.0065 0.0293 309 0.0306 0.0169 0.0859 310 0.0409 0.07110.103 311 0.0148 0.0045 0.0224 312 0.0141 0.0190 0.0675 313 0.01580.0061 0.0509 314 1.6 1.29 NA 315 0.0376 0.231 0.160 316 >2.4 3.07 NA317 0.0067 0.0036 0.0168 318 0.346 0.625 >3.0 319 0.372 0.0099 0.435 3200.0030 0.0037 0.0187 321 0.0334 0.0321 0.0344 322 0.181 0.0456 0.0668323 0.0231 0.0255 0.0377 324 0.0032 0.0012 NA 325 0.155 0.199 0.703 3260.145 0.272 0.286 327 0.0085 0.0042 0.0354 328 0.0245 0.0797 0.0426 3290.0089 0.0126 0.0171 330 0.0509 0.0046 0.0306 331 0.561 0.311 0.481 3320.0304 0.0306 0.0531 333 0.0369 0.0327 0.0740 334 0.661 1.17 0.515 3350.0111 0.0536 0.0224 336 0.0762 0.152 0.115 337 0.0043 0.0042 0.0158 3380.00086 0.0127 0.0779 339 0.00080 0.0316 0.0774 340 0.942 1.25 NA 3410.295 0.0817 0.622 342 0.0719 0.0115 0.510 343 0.0427 0.0048 0.224 3440.430 0.136 0.636 345 0.129 0.0326 0.479 346 0.0962 0.0160 0.213 3470.0156 0.0040 0.0839 348 0.157 0.422 1.0 349 0.0066 0.0031 0.0321 3501.4 0.505 NA 351 0.223 0.153 1.1 352 0.404 0.625 NA 353 0.158 0.2560.786 354 0.066 0.0129 0.0954 *indicates average value of multipleexperiments NA means not determined

TABLE 2 Compound Compound of Example of Example 4 78 Cellular CellularProliferation Proliferation Cell line Type Cell Line EC₅₀ (μM) EC₅₀ (μM)AML SKM1 0.005 0.058 AML Raji 0.006 0.084 Bladder EJ-1 0.202 2.090Breast MDAMB231 0.22 1.22 Breast MDAMB453 0.02 0.24 Colon GEO 0.08 1.29Colon DLD-1 0.20 4.97 Glioblastoma D54MG 0.038 2.299 Head & Neck FaDu0.02 0.39 Hepatocellular HepG2 0.074565 0.8851 Melanoma A-375 0.0203.606 Multiple OPM2 0.001 0.039 Myeloma Multiple RPMI-8226 0.011 1.402Myeloma Multiple NCI-H929 0.003 0.154 Myeloma NHL Ramos 0.02 0.32 NHLLy18 0.02 0.42 NSCLC H1299 0.06 2.57 NSCLC H1975 0.02 1.37 NSCLC H4603.77 >10 Pancreas HPAC 0.05 1.19 Pancreas BxPC3FP5 0.01 0.74 ProstatePC3M 0.07 8.11 RCC 786-0 0.011 0.884 Sarcoma SK-LMS-1 0.025 0.934

Human, Rat, and Mouse Microsome Stability Assay

Microsome stability assays were carried out on compounds of the Exampleslisted in Table 3 (“test compounds”). Human, rat, and mouse livermicrosomal incubations were 5 carried out at 37° C. with a finalincubation volume of 135 μL. Human liver microsomes (mixed gender,Catalog No. H2610) were obtained from XenoTech. Rat liver microsomes(male Sprague-Dawley, Catalog No. 42501) were obtained from BD Gentest.Mouse liver microsomes (male CD1, Catalog No. 452701) were obtained fromBD Gentest. Incubations were conducted using a test compound (initiallydissolved in DMSO at 5 μM concentration) concentration of 0.5 μM and0.25 mg/mL microsomal protein in 50 mM phosphate buffer at pH 7.4. Timezero samples were prepared by transferring 13.5 μL ofcompound-microsomal mix to the quench plates containing 45 μL of quenchsolution made of 10 nM Buspirone (Sigma) or 50 nM Carbutamide (PrincetonBio) as internal standard in 1:1 methanol:acetonitrile. An aliquot of1.5 μL □□ Nicotinamide adenine dinucleotide phosphate reducedtetrasodium salt (NADPH) was also added to the time zero plates. Thereaction was then initiated by the addition of 13.5 μL NADPH to thecompound-microsomal mix. At each of the remaining time points (5, 10,15, 20 and 30 min) 15 μL of incubation mixture was added to 45 μL ofquench solution. Samples were centrifuged for 15-30 minutes at 3800 rpm.Samples were then pooled for 6 per group. An aliquot of 60 μL ofsupernatant was transferred to 384-well plate, and a 5 μL aliquot wasinjected and analyzed by LC-MS/MS (Applied Biosystems API 5500 QTrap).The intrinsic clearance of a compound was calculated by converting thepeak area ratios (analyte peak area/IS peak area) to % parent remainingusing the area ratio at time 0 as 100%. The slope (k) was determinedfrom the plot of the % parent remaining versus incubation time, fromwhich the half life (t_(1/2); minutes), intrinsic clearance (CL_(int);μL/min/mg protein for liver microsomes and μL/min/million cells forhepatocytes) and scaled intrinsic clearance (scaled CL_(int); L/h/kg)were then derived. The t_(1/2) values are reported in Table 3. The term“N/A” means not determined.

TABLE 3 Stability in human Stability in rat liver Stability in mouseCompound liver microsomes microsomes liver microsomes of Ex. No.(t_(1/2) in minutes) (t_(1/2) in minutes) (t_(1/2) in minutes) 1 9 1 1 459 4 57 5 100 6 24 6 30 7 3 7 12 2 4 8 19 1 9 9 NA 1 1 10 78 >120 >12011 48 19 27 12 51 10 33 13 66 2 22 14 37 6 8 15 10 4 7 16 >120 4 22 1731 18 16 18 31 11 15 19 92 13 33 20 18 1 7 21 >120 3 22 22 32 3 10.7 2364 11 >120 24 29 5 55 27 32 >120 59 28 21 9 NA 29 >120 26 >120 3156 >120 19 32 24 82 32 33 >120 >120 46 34 37 42 35 35 37 >120 4236 >120 >120 41 37 88.9 54 3 38 16.8 25 NA 39 09.7 8 NA 40 13.1 1 6 4113.6 1 10 42 >120 >120 >120 43 34.9 2 5 44 33.7 6 27 45 NA 2 3 46 10 413 47 8 3 5 48 37 32 35 49 71 51 46 50 35 88 46 51 6 63 >120 54 3 30 255 25 9 13 56 39 30 36 57 13 6 5 58 >120 1 4 59 >120 40 23 60 68 64 3461 >120 >120 >120 62 64 45 25 63 39 13 18 64 NA 3 4 65 88 >120 1166 >120 >120 NA 67 6 5 6 69 6 2 3 70 41 9 68 71 2 1 6 72 34 1 70 73 36 231 74 17 3 5 75 9 3 4 80 62 2 31 82 19 2 2 83 NA 3 43 84 112 92 >120 8543 6 34 86 >120 >120 43 87 >120 23 NA 88 23 12 NA 91 17 7 7 92 97 20 1193 54 102 25 94 47 28 25 95 >120 7 36 96 24 13 33 97 26 9 28 98 26 33 1099 >120 22 35 100 77 71 60 101 92 12 20 102 36 3 8 103 47 16 37 104 27 87 105 >120 13 7 106 39 8 4 107 71 16 8 108 37 33 13 109 71 61 >120111 >120 42 63 112 49 28 51 114 13 5 8 115 41 38 55 117 34 36 1 118 8134 18 119 14 24 2 >120 19 12 10 121 21 25 24 122 8 16 2 123 >120 >120 45124 2 4 NA 125 45 23 12 126 100 21 25 127 44 71 20 128 11 21 4 129 54 3812 131 >120 71 83 133 4 5 3 134 15 21 2 135 8 24 5 137 38 31 10 138 5251 45 139 13 8 7 140 19 13 18 141 >120 110 49 142 112 35 32 144 18 19 17145 >120 12 16 146 >120 52 55 147 11 8 32 148 58 2 6 152 51 10 22 153 338 11 154 42 66 18 155 >120 >120 25 156 >120 >120 33 157 27 53 12158 >120 >120 >120 159 89 107 59 160 67 119 21 161 5 10 4 162 96 41 11165 >120 111 27 166 85 23 22 168 66 82 25 169 86 34 38 170 >120 113 27171 15 13 9 172 9 15 7 173 38 5 16 174 40 46 14 176 48 8 29 177 16 6 18178 27 7 10 179 80 55 34 180 12 7 5 186 9 3 8 187 9 4 5 188 26 22 6 18934 55 NA 190 27 66 8 191 7 6 2 192 9 5 3 193 11 7 2 194 41 38 49 195 131 1 196 59 5 3 197 16 15 10 198 NA NA 55 199 94 1 3 200 >120 31 >120 20156 117 >120 202 NA >120 NA 203 NA >120 NA 204 >120 81 68 205 >120 81 118206 >120 118 95 207 102 78 100 208 88 23 37 209 >120 105 116 210104 >120 >120 211 65 48 63 212 69 67 53 213 79 38 89 214 27 9 8 215 12 611 217 70 101 68 218 >120 >120 >120 220 5 5 4 221 63 24 43 222 65 80 98223 54 24 48 224 6 8 5 225 52 59 >120 226 105 >120 >120 227 50 70 >120228 >120 107 >120 229 25 33 9 230 6 8 7 231 33 >120 72 232 57 >120 >120235 81 49 22 236 33 32 15 237 3 7 2 238 103 >120 63 240 >120 >120 47 24139 9 4 242 >120 86 >120 243 >120 20 109 244 53 6 87 245 32 24 12 246 5253 56 248 13 16 5 249 >120 >120 >120 250 56 36 37 251 118 23 44 25268 >120 >120 253 72 110 90 254 74 >120 91 255 70 >120 >120 256 58 58 71257 18 56 20.3 258 42 91 69.8 259 117 87 NA 260 34 58 29 261 25 5 16262 >120 25 NA 263 70 72 NA 264 14 6 NA 265 >120 >120 NA 266 8 20 NA 26795 18 >120 268 10 26 NA 269 79 83 58 270 >120 >120 >120 271 23 12 11 2722 4 1 273 9 12 8 276 >120 82 71 277 4 5 1 278 >120 >120 >120 279 NA 4191 280 17 84 36 281 25 119 116 282 9 21 7 283 7 22 12 284 12 108 >120285 19 10 12 286 10 19 11 287 >120 116 29 288 85 >120 >120 290 73 48 52291 16 8 16 292 8 22 12 293 4 9 3 294 >120 >120 >120 295 7 15 3 296 7 136 297 83 43 NA 298 9 47 3 299 1 2 1 300 30 21 17 301 20 82 13 302 5 4 3303 42 69 >120 304 >120 65 72 305 1 2 2 306 11 9 3 307 3 3 2 308 20 1016 309 >120 >120 >120 310 8 5 9 311 >120 83 >120 312 56 32 9 313 5 4 3314 81 4 6 315 34 4 11 316 47 3 12 317 88 115 83 318 35 24 13 319 2 2 2320 >120 57 116 321 >120 103 >120 322 >120 57 >120 323 >120 >120 >120324 >120 >120 >120 325 21 10 8 326 112 5 27 327 >120 >120 >120 328 >12036 >120 329 >120 >120 >120 330 29.9 12 28 331 >120 >120 >120 332 6570 >120 333 0.8 3 1 334 34 NA 21 335 35 34 54 336 44 5 17337 >120 >120 >120 338 39 29 20 339 100 76 67 340 >120 4 9 342 2 5 1 3432 7 1 344 NA NA 1 345 2 4 2 346 4 5 2 347 4 6 NA 348 >120 2 25 349 >12039 36 350 59 32 23 351 76 66 30 353 40 8 10 354 23 41 24

LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay

Compounds of the Examples listed in Table 4 were assayed for theirability to inhibit LPS (lipopolysaccharide) induced IL-6 production inmice. Fox Chase SCID® female mice (Charles Rivers Labs, 8 per group)received an intraperitoneal challenge of lipopolysaccharide (2.5 mg/kg,L2630 E. coli 0111:B4) one hour after oral administration of compounds.Mice were euthanized 2 hours after lipopolysaccharide injection, bloodwas removed by cardiac puncture, and then the serum harvested from theblood samples was frozen at −80° C. On the day of the assay the serumsamples were brought to room temperature and then diluted 1:20 inphosphate-buffered saline containing 2% bovine serum albumin.Interleukin-6 measurements were performed using a cytokine assay fromMeso Scale Discovery (Gaithersburg, Md.) for mouse serum analysisaccording to the manufacturer's protocol and read on a SECTOR Imager6000 (Meso Scale Discovery, Gaithersburg, Md.) instrument. Statisticalanalysis was performed using Prism software (version 5.0) incorporatingDunnett's one way ANOVA. The IL-6 mean and standard deviation of thegroup of vehicle treated animals were compared with the IL-6 mean andstandard deviation of the group treated with test compound. A pvalue<0.05 means that there is less than a 5% probability that the meanvalues in the two groups are equal. The % inhibition values in Table 4all exhibited a p value less than 0.05.

TABLE 4 Inhibition of LPS induced IL-6 production in Mice Example # %inhibition at 3 mg/kg 4 69* 5 74% at 50 mg/kg 11 34 24 58 26 60 27 89 2852 32 69 34 78 36 78* 48 62 49 57 56 28 59 54 62 67 65 63 80 69% at 30mg/kg 84 69 85 80 86 55 87 57 138 72 144 48 146 80 147 61 149 69 150 54151 66 154 73 159 58 160 51 162 41 166 44 167 64 168 70 169 67 197 59198 66 200 75 202 68 203 78 204 35 205 48 207 62 210 78 212 47 231 51238 69 240 62 242 46 245 71 246 71 248 82 249 59 260 66 267 74 273 47276 25 278 51 286 57 287 73 288 60 290 64 294 79 304 67 308 48 311 74321 63 328 40 329 63 330 45 *indicates average value of multipleexperiments

Xenograft Tumor Growth Inhibition Assay

The effect of the compound of Example 36 to inhibit the growth of OPM-2and MX-1 xenograft tumors implanted in mice was evaluated. Briefly,5×10⁶ human cancer cells (OPM-2) or 1:10 tumor brie (MX-1) (in S-MEM(MEM, Suspension, no Calcium, no Glutamine)) (Life TechnologiesCorporation) was inoculated subcutaneously into the right hind flank offemale SCID-beige or female Fox Chase SCID® (Charles River Labs) micerespectively on study day 0. Administration of compound (in (2% EtOH, 5%Tween-80, 20% PEG-400, 73% HPMC)) (PO, QDx14) was initiated at the timeof size match on day 17 (OPM-2) or day 12 (MX-1). The tumors weremeasured by a pair of calipers twice a week starting at the time of sizematch and tumor volumes were calculated according to the formulaV=L×W²/2 (V: volume, mm³; L: length, mm. W: width, mm). Tumor volume wasmeasured for the duration of the experiment until the mean tumor volumein each group reached an endpoint of >1000 mm³ for OPM-2 or until day 27post inoculation for MX-1. Results are shown in Tables 5 and 6.

TABLE 5 OPM-2 human multiple myeloma cancer xenograft model. GroupTreatment Dose route, regimen % TGI^(a) % TGD^(b) 1 Vehicle 0 mg/kg/dayIP, QD×14 — — 2 Compound of 3 mg/kg/day PO, QD×14 90*** 78*** Example 36^(a)Tumor growth inhibition, % TGI = 100 − mean tumor volume oftreatment group/ mean tumor volume of control group × 100. Number ofmice per treatment group = 10. The p values (as indicated by asterisks)are derived from Student's T test comparison of treatment group vs.control group. Based on day 31. *p < 0.05, **p < 0.01, ***p < 0.001.^(b)Tumor growth delay, % TGD = (T − C)/C × 100, where T = median timeto endpoint of treatment group and C = median time to endpoint ofcontrol group. The p values (as indicated by asterisks) derived fromKaplan Meier log-rank comparison of treatment group vs. treatmentcontrol group. Based on an endpoint of 1000 mm³. *p < 0.05, **p < 0.01,***p < 0.001.

TABLE 6 Efficacy of BET inhibitor in the MX-1 human breast cancerxenograft model. Group Treatment Dose route, regimen % TGI^(a) 1 Vehicle0 mg/kg/day PO, QD×14 — 2 Compound of 0.3 mg/kg/day PO, QD×14 43**Examble 36 3 Compound of 1 mg/kg/day PO, QD×14 60*** Example 36 4Compound of 3 mg/kg/day PO, QD×14 76*** Example 36 ^(a)Tumor growthinhibition, % TGI = 100 − mean tumor volume of treatment group/tumorvolume of control group × 100. p values (as indicated by asterisks) arederived from Student's T test comparison of treatment group vs. controlgroup. Based on day 27. *p < 0.05, **p < 0.01, ***p < 0.001.

Xenograft efficacy studies were conducted with additional examplecompounds using OPM-2, MX-1, HT1080, MV4-11, SKM1 and Ramos human cancercells. Cancer cells were prepared from culture or from tumor brie (MX-1)as described above and inoculated subcutaneously into the right hindflank of female SCID-beige mice (OPM-2, HT1080, MV4-11) or female FoxChase SCID (Charles River Labs) mice (MX-1, SKM1, Ramos). Administrationof compound was initiated at the time of size match. Tumors weremeasured by a pair of calipers twice a week starting at the time of sizematch and tumor volumes were calculated according to the formulaV=L×W²/2 (V: volume, mm³; L: length, mm. W: width, mm). Tumor volume wasmeasured for the duration of the experiment until the mean tumor volumein each group reached a model-dependent endpoint of 500-2000 mm³.Results are shown in Table 7.

TABLE 7 Efficacy of BET inhibitors in human xenograft models. % removedCompound dose route, from of Ex. No. model mg/kg/day regimen vehicle^(a)% TGI^(b) % TGD^(c) study 4 MX-1 12.5 PO, BID F 73***  70*** 10 (5 on, 3off) × 2 4 MX-1 25 PO, F 77***  81*** 30 BID (5 on, 3 off) × 2 4 Ramos3.125 PO, F 19  27* 0 BID (5 d on, 3 d off) × 2 4 Ramos 6.25 PO, F 24* 28* 0 BID (5 d on, 3 d off) × 2 27 MX-1 0.3 PO, QD F 38**  35 0 27 MX-11 PO, QD F 57***  13 0 27 MX-1 3 PO, QD F 69*** ND 0 (5 on, 3 off, 5 on)27 OPM-2 1 PO, A 59  −2 0 QD × 14 27 OPM-2 3 PO, QD A 67  7* 0 (5 on, 3off, 5 on) 36 HT1080 0.3 PO, H 26  −1 30 QD × 14 36 HT1080 1 PO, H 41* 3 10 QD × 14 36 HT1080 3 PO, H 47**  46*** 10 QD × 14 36 MV4- 0.2 PO, D22*  16*** 0 11 QD × 21 36 MV4- 0.67 PO, D 57***  59*** 0 11 QD × 21 36MV4- 2 PO, D 81***  94* 0 11 QD × 21 cytarabine MV4- 250 IP, BID C 47*** 37*** 0 11 Q7D × 3 36/ MV4- 0.67/250  PO/IP, E 64***  53*** 0cytarabine 11 QD × 21/ BID Q7D × 3 36/ MV4-  2/250 PO/IP, E 90*** 102***0 cytarabine 11 QD × 21/ BID Q7D × 3 36 MX-1 0.3 PO, QD F 43**  40 0 36MX-1 1 PO, QD F 60*** ND 0 36 MX-1 3 PO, QD F 76*** ND 0 36 OPM-2 0.25PO, A 19  29 0 QD × 21 36 OPM-2 0.25 IP, F 45  55* 0 QD × 21 36 OPM-20.5 PO, A 75*** 101*** 0 QD × 21 36 OPM-2 0.5 IP, F 49*  52** 0 QD × 2136 OPM-2 1 PO, A 75*** 107*** 10 QD × 21 36 OPM-2 1 PO, A 72**  64* 10QD × 21 36 OPM-2 1 PO, A 79*** 140*** 0 QD × 21 36 OPM-2 1 PO, A 74***140*** 10 BID × 21 36 OPM-2 1 PO, A 70**  85** 0 QD × 21 36 OPM-2 1 IV,C 69**  66** 0 Q4D × 3 36 OPM-2 1 IP, F 61*  80*** 0 Q4D × 3 36 OPM-2 1IV, C 80** 112*** 0 Q4D × 3 36 OPM-2 2 PO, A 60 QD × 21 36 OPM-2 3 PO, A90***  21*** 10 QD × 14 36 OPM-2 3 PO, A 88*** 131*** 30 QD × 21 36OPM-2 3 PO, A 70 BID × 21 d 36 OPM-2 3 IP, F 40 QD × 21 36 OPM-2 3 IP, F70 QD × 21 36 OPM-2 4.2 PO, A 50 QD(5 on 2 off) × 3 36 OPM-2 5.25 PO, A40 QD(4 on 3 off) × 3 36 OPM-2 6 PO, A 82*  84** 20 Q2D × 21 d 36 OPM-26 IP, F 100 QD × 21 36 OPM-2 7 PO, A 81***  97*** 0 QD(3 on 4 off) × 336 OPM-2 7 PO, A 90 BID (3 on 4 off) × 3 36 OPM-2 10.5 PO, A 75*** 94*** 0 QD(2 on 5 off) × 3 Bortezomib OPM-2 1 IV, B 80**  93*** 10 Q4D× 3 36/ OPM-2 0.25/1   IP/IV, B 94** 195*** 20 Bortezomib QD × 21/ Q4D ×3 36/ OPM-2 0.5/1   IP/IV, B 40 Bortezomib QD × 21/ Q4D × 3 36/ OPM-21/1 PO/IV, B 100 Bortezomib QD × 21/ Q4D × 3 36/ OPM-2 1/1 IP/IV, G 40Bortezomib QD × 21/ Q4D × 3 36 SKM1 0.2 PO, A 41*  93 0 QD × 21 36 SKM10.67 PO, A 58* 444*** 0 QD × 21 36 SKM1 2 PO, A 86** 721*** 0 QD × 21azacitidine SKM1 6 IV, C 54**  98* 0 Q7D × 3 36/ SKM1 0.67/6   PO/IV, B86** 649*** 10 azacitidine QD × 21/ Q7D × 3 36/ SKM1 2/6 PO/IV, B 91**958*** 10 azacitidine QD × 21/ Q7D × 3 cytarabine SKM1 250 IP, BID C 20 30 0 Q7D × 3 36/ SKM1 0.67/250  PO/IP, B 69** 514*** 0 cytarabine QD ×21/ BID Q7D × 3 36/ SKM1  2/250 PO/IP, B 87** 739*** 0 cytarabine QD ×21/ BID Q7D × 3 146 OPM-2 1 PO, A 39  35 10 QD × 21 146 OPM-2 3 PO, A76*  78** 0 QD × 21 158 OPM-2 6 PO, A 53  34 10 QD × 21 158 OPM-2 20 PO,A 78*  72** 30 QD × 21 169 OPM-2 3 PO, A 69*  77* 10 QD × 21 169 OPM-210 PO, A 100 QD × 21 200 OPM-2 1 PO, A 50  44 10 QD × 21 200 OPM-2 3 PO,A 80**  82** 20 QD × 21 250 OPM-2 3 PO, A 42**  29 0 QD × 21 250 OPM-210 PO, A 40 QD × 21 287 OPM-2 10 PO, A 50 QD × 21 287 OPM-2 20 PO, A 70QD × 21 311 OPM-2 1.25 PO, A 60*  90* 0 QD × 21 311 OPM-2 2.5 PO, A 56QD × 21 ^(a)Compounds were formulated in the following vehicles: A: 10%EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG) B: 10% EtOH, 30% PEG400, 60% Phosol 53 MCT (Lipoid AG)/0.9% Saline C: 0.9% Saline D: 10%EtOH, 27.5% PEG 400, 60% Phosol 53 MCT (Lipoid AG) E: 10% EtOH, 27.5%PEG 400, 60% Phosol 53 MCT (Lipoid AG)/0.9% Saline F: 2% EtOH, 5%Tween-80, 20% PEG400, 73% 0.2% HPMC G: 2% EtOH, 5% Tween-80, 20% PEG400,73% 0.2% HPMC/0.9% Saline and H: 5% EtOH, 30% PEG 400, 60% Phosol 53 MCT(Lipoid AG) ^(b)Tumor growth inhibition, % TGI = 100 − mean tumor volumeof treatment group/mean tumor volume of control group × 100. Number ofmice per treatment group = 8 (MX-1, MV4-11, SKM1) or 10 (OPM-2). The pvalues (as indicated by asterisks) are derived from Student's T testcomparison of treatment group vs. control group. Based on day 31. *p <0.05, **p < 0.01, ***p < 0.001. % TGI values are not presented ifmortality □40%. ^(c)Tumor growth delay, % TGD = (T − C)/C × 100, where T= median time to endpoint of treatment group and C = median time toendpoint of control group. The p values (as indicated by asterisks)derived from Kaplan Meier log-rank comparison of treatment group vs.treatment control group. *p < 0.05, **p < 0.01, ***p < 0.001. % TGDvalues are not presented if mortality □40%. ND = Not determined

In Vivo Rat Collagen Induced Arthritis Model

Compound of Example 36 inhibits paw swelling in a rat collagen inducedarthritis (rCIA) model of inflammation. On day 0 of the rCIA modelfemale Lewis rats (n=9/group) were immunized intradermally (id) with 600μg of bovine type II collagen in an emulsion with incomplete Freund'sadjuvant (IFA). Immunization was given over three sites receiving a 100μL intradermal injection at each site. On day 6 rats were boosted with600 μg of bovine type II collagen in a manner identical to the initialimmunization protocol. A control group of rats received the same volumeof IFA alone, also on day 0 and day 6. Using a plethysmograph waterdisplacement system paw volume was measured on day 7 (baselinemeasurement) and on days 10, 12, 14 and 17. Dose groups included IFAimmunized non-arthritic rats, PBS vehicle treated, prednisolone treated(3 mg/kg positive control), compound vehicle treated (10% EtOH/30%PEG400/60% Phosal 53) and Example 36 dosed orally at 1.0, 0.3, 0.1, and0.03 mg/kg. Dosing began on day 10 and animals were treated once dailythrough day 17 via oral dosing with a 1.0 mL volume. Paw swelling isreported as change in paw volume from baseline and area under the curve(AUC) was calculated for the paw swelling in each dose group. Example 36inhibited inflammation in the arthritic paw in a dose dependent mannerwith an ED₅₀ of 0.21 mg/kg and an ED₅₀ of 0.69 mg/kg corresponding tomaximum plasma concentrations of 6.8 ng/mL and 22.3 ng/mL at the ED₅₀and ED₅₀, respectively.

TABLE 8 AUC of Paw Swelling (ml-day) Treatment group MEAN SEM IFAimmunized (non- 0.13** 0.06 arthritic) PBS Vehicle 4.33 0.49 Compoundvehicle 4.90 0.32 Example 36 dosed at 1.0 mg/kg 0.70** 0.16 Example 36dosed at 0.3 mg/kg 1.84** 0.23 Example 36 dosed at 3.66* 0.21 0.1 mg/kgExample 36 dosed at 4.19 0.34 0.03 mg/kg Prednisolone dosed at 0.67**0.20 3 mg/kg One way Anova (vs. compound vehicle) *p < 0.05 **p < 0.001

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof. All publications, patents, and patent applications citedherein are hereby incorporated by reference in their entirety for allpurposes.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof

wherein R^(x) is hydrogen or C₁-C₃ alkyl; R^(y) is C₁-C₃ alkyl, —(C₂-C₃alkylenyl)-OH, or C₁-C₃ haloalkyl; X¹ is N or CR^(x1) wherein R^(x1) ishydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax1),—C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), S(O)₂R^(dx1), —S(O)₂NR^(bx1)R^(cx1),G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl isoptionally substituted with one substituent selected from the groupconsisting of OR^(ax1), SR^(ax1), S(O)R^(dx1), S(O)₂R^(dx1),NR^(bx1)R^(cx1), —C(O)R^(ax1), —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1),—S(O)₂NR^(bx1)R^(cx1), and G^(x1); R^(ax1), R^(bx1), and R^(cx1), ateach occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a); R^(dx1), at eachoccurrence, are each independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a),or —(C₁-C₆ alkylenyl)-G^(a); X² is N or CR^(x2); wherein R² is hydrogen,C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax2), —C(O)NR^(bx2)R^(cx2),—C(O)R^(dx2), —C(O)H, S(O)₂R^(dx2), —S(O)₂NR^(bx2)R^(cx2), G^(x2), C₁-C₆haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl is optionallysubstituted with one substituent selected from the group consisting ofOR^(ax2), SR^(ax2), S(O)R^(dx2), S(O)₂R^(dx2), NR^(bx2)R^(cx2),—C(O)R^(ax2), —C(O)OR^(ax2), —C(O)NR^(bx2)R^(cx2),—S(O)₂NR^(bx2)R^(cx2), and G^(x2); R^(ax2), R^(bx2), and R^(cx2), ateach occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, G^(b), or —(C₁-C₆ alkylenyl)-G^(b); R^(dx2), at eachoccurrence, is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(b), or—(C₁-C₆ alkylenyl)-G^(b); Y¹ is N or CR^(u); wherein R^(u) is hydrogen,C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; A¹ is N or CR¹, A² is N orCR², A³ is N or CR³; and A⁴ is N or CR⁴; with the proviso that zero,one, two, or three of A¹, A², A³, and A⁴ are N; R¹, R³, and R⁴ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, C₁-C₆ haloalkyl, CN, or NO₂; R² is hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a),—OR^(2a), —OC(O)R^(2d), —OC(O)NR^(2b)R^(2c), —SR^(2a), —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a), —C(O)NR^(2b)R^(2c),—NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d), —N(R^(2e))S(O)₂R^(2d),—N(R^(2e))C(O)O(R^(2d)), —N(R^(2e))C(O)NR^(2b)R^(2c),—N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆alkylenyl)-OR^(2a), —(C₁-C₆ alkylenyl)-OC(O)R^(2d), —(C₁-C₆alkylenyl)-OC(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d), —(C₁-C₆alkylenyl)-C(O)OR^(2a), —(C₁-C₆ alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),—(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)O(R^(2a)), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c), and —(C₁-C₆ alkylenyl)-CN;R^(2a), R^(2b), R^(2c), and R^(2e), at each occurrence, are eachindependently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,G^(2b), or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substitutedwith one substituent selected from the group consisting of —OR^(z1),NR^(z1)R^(z2), —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),—S(O)₂NR^(z1)R^(z2), and G^(2b); R^(2d), at each occurrence, isindependently C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2b), orC₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted with onesubstituent selected from the group consisting of —OR^(z1),NR^(z1)R^(z2), —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),—S(O)₂NR^(z1)R^(z2), and G^(2b); R^(z1) and R^(z2), at each occurrence,are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;G^(x1), G^(x2), G^(a), G^(b), G^(2a), and G^(2b), at each occurrence,are each independently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl, and each of which is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 of R^(v); L¹ is absent, CH₂, C(O),C(H)(OH), (CH₂)_(m)O, (CH₂)_(m)S(O)_(n) wherein n is 0, 1, or 2; or(CH₂)_(m)N(R^(z)) wherein R^(z) is hydrogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, (C₂-C₃ alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or1; G¹ is C₁-C₆ alkyl, alkoxyalkyl, G^(1a) or —(C₁-C₆ alkylenyl)-G^(1a);wherein each G^(1a) is independently aryl, heteroaryl, heterocycle,cycloalkyl, or cycloalkenyl, and each G^(1a) is independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 of R^(w); R^(v) andR^(w), at each occurrence, are each independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —OR^(h),—OC(O)R^(i), —OC(O)NR^(j)R^(k), —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k),—C(O)R^(h), —C(O)-monocyclic heterocycle, —C(O)-monocyclic heteroaryl,—C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R^(i),—N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)), —N(R^(h))C(O)NR^(j)R^(k),—(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆ alkylenyl)-OC(O)R^(i), —(C₁-C₆alkylenyl)-OC(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-S(O)₂R^(h), —(C₁-C₆alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆ alkylenyl)-C(O)R^(h), —(C₁-C₆alkylenyl)-C(O)OR^(h), —(C₁-C₆ alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆alkylenyl)-NR^(j)R^(k), —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆ alkylenyl)-N(R^(h))C(O)O(R^(i)),—(C₁-C₆ alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN;R^(h), R^(j), R^(k), at each occurrence, are each independentlyhydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and R^(i), at eachoccurrence, is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl.
 2. Acompound of formula (I) or a pharmaceutically acceptable salt thereof

wherein R^(x) is hydrogen or C₁-C₃ alkyl; R^(y) is C₁-C₃ alkyl, —(C₂-C₃alkylenyl)-OH, or C₁-C₃ haloalkyl; X¹ is N or CR^(x1) wherein R^(x1) ishydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax1),—C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), S(O)₂R^(dx1), —S(O)₂NR^(bx1)R^(cx1),G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl isoptionally substituted with one substituent selected from the groupconsisting of OR^(ax1), SR^(ax1), S(O)R^(dx1), S(O)₂R^(dx1),NR^(bx1)R^(cx1), —C(O)R^(ax1), —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1),—S(O)₂NR^(bx1)R^(cx1), and G^(x1); R^(ax1), R^(bx1), and R^(cx1), ateach occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a); R^(dx1), at eachoccurrence, are each independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a),or —(C₁-C₆ alkylenyl)-G^(a); X² is N or CR^(x2); wherein R^(x2) ishydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax2),—C(O)NR^(bx2)R^(cx2), —C(O)R^(dx2), S(O)₂R^(dx2), —S(O)₂NR^(bx2)R^(cx2),G^(x2), C₁-C₆ haloalkyl, or C₁-C₆ alkyl; wherein the C₁-C₆ alkyl isoptionally substituted with one substituent selected from the groupconsisting of OR^(ax2), SR^(ax2), S(O)R^(dx2), S(O)₂R^(dx2),NR^(bx2)R^(cx2), —C(O)R^(ax2), —C(O)OR^(ax2), —C(O)NR^(bx2)R^(cx2),—S(O)₂NR^(bx2)R^(cx2), and G^(x2); R^(ax2), R^(bx2), and R^(cx2), ateach occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, G^(b), or —(C₁-C₆ alkylenyl)-G^(b); R^(dx2), at eachoccurrence, is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(b), or—(C₁-C₆ alkylenyl)-G^(b); Y¹ is N or CR^(u); wherein R^(u) is hydrogen,C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; A¹ is N or CR¹, A² is N orCR², A³ is N or CR³; and A⁴ is N or CR⁴; with the proviso that zero,one, two, or three of A¹, A², A³, and A⁴ are N; R¹, R³, and R⁴ are eachindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, C₁-C₆ haloalkyl, CN, or NO₂; R² is hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a),—OR^(2a), —OC(O)R^(2d), —OC(O)NR^(2b)R^(2c), —SR^(2a), —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a), —C(O)NR^(2b)R^(2c),—NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d), —N(R^(2e))S(O)₂R^(2d),—N(R^(2e))C(O)O(R^(2d)), —N(R^(2e))C(O)NR^(2b)R^(2c),—N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆alkylenyl)-OR^(2a), —(C₁-C₆ alkylenyl)-OC(O)R^(2d), —(C₁-C₆alkylenyl)-OC(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d), —(C₁-C₆alkylenyl)-C(O)OR^(2a), —(C₁-C₆ alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),—(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)O(R^(2a)), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c), and —(C₁-C₆ alkylenyl)-CN;R^(2a), R^(2b), R^(2c), and R^(2e), at each occurrence, are eachindependently hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,G^(2b), or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substitutedwith one substituent selected from the group consisting of —OR^(z1),NR^(z1)R^(z2), —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),—S(O)₂NR^(z1)R^(z2), and G^(2b); R^(2d), at each occurrence, isindependently C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2b), orC₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionally substituted with onesubstituent selected from the group consisting of —OR^(z1),NR^(z1)R^(z2), —C(O)OR^(z1), —C(O)NR^(z1)R^(z2), —S(O)₂R^(z1),—S(O)₂NR^(z1)R^(z2), and G^(2b); R^(z1) and R^(z2), at each occurrence,are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;G^(x1), G^(x2), G^(a), G^(b), G^(2a), and G^(2b), at each occurrence,are each independently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl, and each of which is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 of R^(v); L¹ is absent, CH₂, C(O),(CH₂)_(m)O, (CH₂)_(m)S(O)_(n) wherein n is 0, 1, or 2; or(CH₂)_(m)N(R^(z)) wherein R^(z) is hydrogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, (C₂-C₃ alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or1; G¹ is G^(1a) or —(C₁-C₆ alkylenyl)-G^(1a); wherein each G^(1a) isindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl, and each G^(1a) is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 of R^(w); R^(v) and R^(w), at eachoccurrence, are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, C₁-C₆ haloalkyl, —CN, oxo, —OR^(h), —OC(O)R^(i),—OC(O)NR^(j)R^(k), —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k), —C(O)R^(h),—C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R^(i),—N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)), —N(R^(h))C(O)NR^(j)R^(k),—(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆ alkylenyl)-OC(O)R^(i), —(C₁-C₆alkylenyl)-OC(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-S(O)₂R^(h), —(C₁-C₆alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆ alkylenyl)-C(O)R^(h), —(C₁-C₆alkylenyl)-C(O)OR^(h), —(C₁-C₆ alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆alkylenyl)-NR^(j)R^(k), —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆ alkylenyl)-N(R^(h))C(O)O(R^(i)),—(C₁-C₆ alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN;R^(h), R^(j), R^(k), at each occurrence, are each independentlyhydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and R^(i), at eachoccurrence, is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl.
 3. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R^(y) is C₁-C₃ alkyl.
 4. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R^(y) is methyl. 5.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein X¹ is CR^(x1); and X² is CR^(x2).
 6. The compound of claim 1 ora pharmaceutically acceptable salt thereof, wherein Y¹ is N.
 7. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein Y¹ is CR^(u).
 8. The compound of claim 6 or a pharmaceuticallyacceptable salt thereof, wherein R^(u) is hydrogen or C₁-C₃ alkyl. 9.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein L¹ is CH₂, C(O), (CH₂)_(m)O, or (CH₂)_(m)N(R^(z)).
 10. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein L¹ is (CH₂)_(m)O and G¹ is G^(1a).
 11. The compound of claim 1or a pharmaceutically acceptable salt thereof, wherein A¹ is CR¹; A² isCR²; A³ is CR³; and A⁴ is CR⁴.
 12. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein one of A¹, A², A³, andA⁴ is N.
 13. The compound of claim 1 or a pharmaceutically acceptablesalt thereof, wherein R² is hydrogen, C₁-C₆ alkyl, NO₂, G^(2a),—S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a),—C(O)NR^(2b)R^(2c), —NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d),—N(R^(2e))S(O)₂R^(2d), —N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(2a), —(C₁-C₆alkylenyl)-S(O)₂R^(2d), —(C₁-C₆ alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-C(O)R^(2d), —(C₁-C₆ alkylenyl)-C(O)OR^(2a), —(C₁-C₆alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-N(R^(2e))C(O)R^(2d), —(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d),or —(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c).
 14. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein R² is—S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)NR^(2b)R^(2c),—N(R^(2e))C(O)R^(2d), —N(R^(2e))S(O)₂R^(2d),—N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d), —(C₁-C₆alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),—(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c).
 15. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—N(R^(2e))S(O)₂NR^(2b)R^(2c).
 16. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein Y¹ is N; X¹ isCR^(x1); and X² is CR^(x2).
 17. The compound of claim 16 or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of: ethyl4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate;ethyl4-[5-(ethylamino)-2-phenoxyphenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate;ethyl4-{5-[ethyl(methylsulfonyl)amino]-2-phenoxyphenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate;6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylicacid;6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;6-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl)}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-phenoxyphenyl]methanesulfonamide;N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one;N-ethyl-N,6-dimethyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)phenyl]methanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)phenyl]ethanesulfonamide;and4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one.18. The compound of claim 16 or a pharmaceutically acceptable saltthereof, wherein R^(y) is methyl.
 19. The compound of claim 18 or apharmaceutically acceptable salt thereof, wherein L¹ is CH₂, C(O),(CH₂)_(m)O, or (CH₂)_(m)N(R^(z)).
 20. The compound of claim 18, or apharmaceutically acceptable salt thereof, wherein L¹ is (CH₂)_(m)O. 21.The compound of claim 20 or a pharmaceutically acceptable salt thereof,wherein G¹ is G^(1a).
 22. The compound of claim 21 or a pharmaceuticallyacceptable salt thereof, wherein G^(1a) is optionally substituted aryl.23. The compound of claim 21 or a pharmaceutically acceptable saltthereof, wherein G^(1a) is optionally substituted phenyl.
 24. Thecompound of claim 21 or a pharmaceutically acceptable salt thereof,wherein G^(1a) is optionally substituted cycloalkyl.
 25. The compound ofclaim 21 or a pharmaceutically acceptable salt thereof, wherein G^(1a)is optionally substituted monocyclic cycloalkyl.
 26. The compound ofclaim 21 or a pharmaceutically acceptable salt thereof, wherein G^(1a)is optionally substituted heterocycle.
 27. The compound of claim 21 or apharmaceutically acceptable salt thereof, wherein G^(1a) is optionallysubstituted monocyclic heterocycle.
 28. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein Y¹ is CR^(u); X¹ isCR^(x1); and X² is CR^(x2).
 29. The compound of claim 28 or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(5-amino-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]acetamide;N-methyl-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;ethyl3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoate;3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzoicacid;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-3-yloxy)phenyl]methanesulfonamide;6-methyl-4-[2-(morpholin-4-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(tetrahydrofuran-2-ylmethyl)benzamide;N-cyclopentyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;N-(2,2-difluoroethyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(1,3-thiazol-2-yl)benzamide;N-(1,1-dioxidotetrahydrothiophen-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide;4-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]ethanesulfonamide;N,N-dimethyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]sulfuricdiamide;N-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxypyridin-3-yl]methanesulfonamide;N-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;N-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl]methanesulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]methanesulfonamide;6-methyl-4-[2-phenoxy-5-(1H-pyrazol-1-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]methanesulfonamide;N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(trifluoromethyl)phenoxy]phenyl}methanesulfonamide;N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]aceticacid;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-3,3,3-trifluoropropanamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2,2-dimethylpropanamide;ethyl4-(cyclopentylamino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate;4-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzyl]amino}-4-oxobutanoicacid;4-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(benzyloxy)-5-(2-hydroxyethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;methyl[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetate;2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-ethylacetamide;2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N,N-dimethylacetamide;N-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]methanesulfonamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydrofuran-3-yl)benzamide;4-{2-(2,4-difluorophenoxy)-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(1-methyl-2-oxopyrrolidin-3-yl)benzamide;tert-butyl{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]pyrrolidin-3-yl}carbamate;4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylcarbonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylcarbonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]methanesulfonamide;6-methyl-4-[2-(morpholin-4-ylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide;N-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N′-methylsulfuricdiamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide;methyl6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;methyl1,6-dimethyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;ethyl4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid; ethyl6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-{4-[(ethylsulfonyl)amino]-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy}benzamide;6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;6-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-{3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-phenoxyphenyl}methanesulfonamide;N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)phenyl]propane-1-sulfonamide;N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]propane-1-sulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]propane-1-sulfonamide;3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzenesulfonamide;6-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;6-(cyclohexylamino)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;N-methyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]sulfuricdiamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamide;2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide;N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide;N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}propane-1-sulfonamide;N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}-2,2,2-trifluoroethanesulfonamide;N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}-N′-methylsulfuricdiamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]propane-1-sulfonamide;2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide;N-methyl-N′-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]sulfuricdiamide;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide;N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamide;N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamino)pyridine-3-sulfonamide;N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide;2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]propane-1-sulfonamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyrimidin-2-yl)benzamide;4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridin-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-(2,4-difluorophenoxy)-N-(1H-indazol-6-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-[2-(2,4-difluorophenoxy)-5-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-4-ylmethyl)benzamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide;4-(2,4-difluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;N-(3,4-difluorobenzyl)-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide;2-{4-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]piperazin-1-yl}-N,N-dimethylacetamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-2-ylmethyl)benzamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(3,4,5-trimethoxybenzyl)benzamide;4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;N-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-(2,4-difluorophenoxy)-N-[2-(1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;4-[2-(2,4-difluorophenoxy)-5-{[4-(furan-2-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;tert-butyl{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]piperidin-4-yl}carbamate;tert-butyl4-{[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoyl]amino}piperidine-1-carboxylate;4-[2-(2,4-difluorophenoxy)-5-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(4-chlorobenzoyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimidin-5-yloxy)phenyl]ethanesulfonamide;N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-methyl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamide;N-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide;N-[4-(2,2-dimethylpropoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;4-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(4-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(3-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(4-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile;4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile;6-methyl-4-{5-(methylsulfonyl)-2-[3-(trifluoromethyl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(isoquinolin-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-6-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[2-chloro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[2-fluoro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;2-{4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}acetamide;4-[2-(3-aminophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylamino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(1-methylpiperidin-4-yl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,1,3-benzothiadiazol-4-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(isoquinolin-7-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(3,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-(4-methylphenoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2-methoxyphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{2-[(2-methylpyridin-3-yl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[3-(dimethylamino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[(3-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;2-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzonitrile;4-[2-(3-chloro-2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(naphthalen-1-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2-fluoro-5-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(5-fluoro-2-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-7-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(4-chloro-3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(pyridin-3-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,3-dihydro-1H-inden-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[4-(propan-2-yl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(isoquinolin-8-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(3,4,5-trifluorophenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(2-benzylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(biphenyl-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(4-oxocyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-yloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(3-fluorooxetan-3-yl)methoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;6-(cyclopropylmethoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;6-[(cyclopropylmethyl)amino]-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclobutyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopentylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopentyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxoimidazolidin-1-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2-cyclopropylethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cycloheptyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-(2-methylpropoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{2-[(2-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclohexylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{2-[2-(1-methylpyrrolidin-2-yl)ethoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[2-(morpholin-4-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(1-tert-butoxypropan-2-yl)oxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(1S,4R)-bicyclo[2.2.1]hept-2-ylmethoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{2-[(1-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{2-[(4-methylcyclohexyl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclobutylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]cyclopropanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-methoxyethanesulfonamide;6-methyl-4-{5-(methylsulfonyl)-2-[tricyclo[3.3.1.1^(3,7)]dec-2-yloxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;4-[(cyclopropylmethyl)amino]-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;4-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;6-(2,4-difluorophenoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;4-[2-(cyclopropylmethoxy)-6-methylphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;4-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-4-ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(1,3-thiazol-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;ethyl4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]piperidine-1-carboxylate;4-[2-ethoxy-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;N-[4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;4-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;4-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N,N,6-trimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;6-methyl-4-{5-(methylsulfonyl)-2-[4-(methylsulfonyl)phenoxy]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide;4-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,3-dihydro-1H-inden-2-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-[(dimethylamino)methyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-4-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methylpiperazin-1-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(phenylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(1,3-thiazol-2-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(tetrahydrofuran-3-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin-3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(prop-1-en-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(phenoxymethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide;4-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-2-(dimethylamino)ethanesulfonamide;ethyl4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate;4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]benzonitrile;4-[2-(cyclopropylmethoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[2-(2-hydroxyethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-{[3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;tert-butyl4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate;4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-phenylbenzenesulfonamide;4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(pyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{5-(ethylsulfonyl)-2-[3-(hydroxymethyl)phenoxy]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;tert-butyl4-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate;4-[5-(6-aminopyridin-3-yl)-2-(cyclopropylmethoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[5-(ethylsulfonyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide;4-[4-(cyclopropylmethoxy)-3′-fluorobiphenyl-3-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]acetonitrile;N-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;4-[2-(cyclopropylmethoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(pyridin-2-ylmethyl)ethanesulfonamide;N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide;4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide;4-[2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-{4-(2,4-difluorophenoxy)-3-[6-methyl-3-(morpholin-4-ylmethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-{6-methyl-3-[(4-methylpiperazin-1-yl)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;4-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4′-(cyclopropylmethoxy)-3′-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)biphenyl-3-carbonitrile;and4-{2-(cyclopropylmethoxy)-5-[(4-hydroxypiperidin-1-yl)sulfonyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.30. The compound of claim 28 or a pharmaceutically acceptable saltthereof, wherein R^(y) is methyl.
 31. The compound of claim 30 or apharmaceutically acceptable salt thereof, wherein L¹ is CH₂, C(O),(CH₂)_(m)O, or (CH₂)_(m)N(R^(z)).
 32. The compound of claim 30 or apharmaceutically acceptable salt thereof, wherein L¹ is (CH₂)_(m)O. 33.The compound of claim 32 or a pharmaceutically acceptable salt thereof,wherein G¹ is G^(1a).
 34. The compound of claim 33 or a pharmaceuticallyacceptable salt thereof, wherein G^(1a) is optionally substituted aryl.35. The compound of claim 33 or a pharmaceutically acceptable saltthereof, wherein G^(1a) is optionally substituted phenyl.
 36. Thecompound of claim 33 or a pharmaceutically acceptable salt thereof,wherein G^(1a) is optionally substituted cycloalkyl.
 37. The compound ofclaim 33 or a pharmaceutically acceptable salt thereof, wherein G^(1a)is optionally substituted monocyclic cycloalkyl.
 38. The compound ofclaim 33 or a pharmaceutically acceptable salt thereof, wherein G^(1a)is optionally substituted heterocycle.
 39. The compound of claim 33 or apharmaceutically acceptable salt thereof, wherein G^(1a) is optionallysubstituted monocyclic heterocycle.
 40. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein Y¹ is CR^(u); X¹ is N;X² is CR^(x2); and R^(y) is methyl.
 41. The compound of claim 40 or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting ofN-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl]ethanesulfonamide;4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;and4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;or a pharmaceutically acceptable salt thereof.
 42. The compound of claim16, or a pharmaceutically acceptable salt thereof, wherein A¹ is CR¹, A²is CR², A³ is CR³, and A⁴ is CR⁴; or one of A¹, A², A³, and A⁴ is N. 43.The compound of claim 42 or a pharmaceutically acceptable salt thereof,wherein R² is hydrogen, C₁-C₆ alkyl, NO₂, G^(2a), —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —C(O)R^(2d), —C(O)OR^(2a), —C(O)NR^(2b)R^(2c),—NR^(2b)R^(2c), —N(R^(2e))C(O)R^(2d), —N(R^(2e))S(O)₂R^(2d),—N(R^(2e))S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆alkylenyl)-OR^(2a), —(C₁-C₆ alkylenyl)-S(O)₂R^(2d), —(C₁-C₆alkylenyl)-S(O)₂NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-C(O)R^(2d), —(C₁-C₆alkylenyl)-C(O)OR^(2a), —(C₁-C₆ alkylenyl)-C(O)NR^(2b)R^(2c), —(C₁-C₆alkylenyl)-NR^(2b)R^(2c), —(C₁-C₆ alkylenyl)-N(R^(2e))C(O)R^(2d),—(C₁-C₆ alkylenyl)-N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)-N(R^(2e))S(O)₂NR^(2b)R^(2c).
 44. The compound of claim 42 ora pharmaceutically acceptable salt thereof, wherein R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—N(R^(2e))S(O)₂NR^(2b)R^(2c).
 45. The compound of claim 44 or apharmaceutically acceptable salt thereof, wherein R^(x) is hydrogen ormethyl.
 46. The compound of claim 44 or a pharmaceutically acceptablesalt thereof, wherein R^(x) is hydrogen.
 47. The compound of claim 46 ora pharmaceutically acceptable salt thereof, wherein R^(x1) is hydrogen,—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), G^(x1), or C₁-C₆ alkyl wherein theC₁-C₆ alkyl is optionally substituted with OR^(ax1).
 48. The compound ofclaim 46 or a pharmaceutically acceptable salt thereof, wherein R^(x1)is hydrogen, —C(O)OR^(ax1), or —C(O)NR^(bx1)R^(cx1).
 49. The compound ofclaim 48 or a pharmaceutically acceptable salt thereof, wherein R^(x2)is hydrogen.
 50. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R^(x) is hydrogen; R^(y) is methyl; Y¹is CR^(u) wherein R^(u) is hydrogen; X¹ is CR^(x1) wherein R^(x1) ishydrogen or —C(O)NR^(bx1)R^(cx1); X² is CR^(x2) wherein R^(x2) ishydrogen; L¹ is (CH₂)_(m)O wherein m is 0; G¹ is G^(1a) or —(C₁-C₆alkylenyl)-G^(1a), wherein G^(1a) is optionally substituted phenyl oroptionally substituted cycloalkyl; and R² is —S(O)₂R^(2d),—S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or —(C₁-C₆alkylenyl)-S(O)₂R^(2d).
 51. The compound of claim 50 or apharmaceutically acceptable salt thereof, wherein A¹ is CR¹, A² is CR²,A³ is CR³, and A⁴ is CR⁴.
 52. The compound of claim 50 or apharmaceutically acceptable salt thereof, wherein A¹ is CR¹, A² is CR²,A³ is CR³, and A⁴ is N.
 53. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R^(x) is hydrogen;R^(y) is methyl; Y¹ is CR^(u) wherein R^(u) is hydrogen; X¹ is CR^(x1)wherein R^(x1) is hydrogen; X² is CR² wherein R^(x2) is hydrogen; L¹ is(CH₂)_(m)N(R^(z)) wherein m is 0 and R^(z) is hydrogen; G¹ is —(C₁-C₆alkylenyl)-G^(1a), wherein G^(1a) is optionally substituted cycloalkyl;and R² is —S(O)₂R^(2d), —S(O)₂NR^(2b)R^(2c), —N(R^(2e))S(O)₂R^(2d), or—(C₁-C₆ alkylenyl)-S(O)₂R^(2d).
 54. The compound of claim 53 or apharmaceutically acceptable salt thereof, wherein A¹ is CR¹, A² is CR²,A³ is CR³, and A⁴ is CR⁴.
 55. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier.
 56. A method fortreating cancer in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, to a subject in need thereof.57. The method of claim 56 wherein the cancer is selected from the groupconsisting of: acoustic neuroma, acute leukemia, acute lymphocyticleukemia, acute myelocytic leukemia (monocytic, myeloblastic,adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic andpromyelocytic), acute t-cell leukemia, basal cell carcinoma, bile ductcarcinoma, bladder cancer, brain cancer, breast cancer, bronchogeniccarcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma,chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic(granulocytic) leukemia, chronic myelogenous leukemia, colon cancer,colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse largeB-cell lymphoma, dysproliferative changes (dysplasias and metaplasias),embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma,epithelial carcinoma, erythroleukemia, esophageal cancer,estrogen-receptor positive breast cancer, essential thrombocythemia,Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicularcancer, glioma, glioblastoma, gliosarcoma, heavy chain disease,hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitiveprostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.
 58. The method of claim 56, further comprisingadministering a therapeutically effective amount of at least oneadditional therapeutic agent, wherein the additional therapeutic agentis selected from the group consisting of cytarabine, bortezomib, and5-azacitidine.
 59. A method for treating a disease or condition in asubject comprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof, wherein saiddisease or condition is selected from the group consisting of: Addison'sdisease, acute gout, ankylosing spondylitis, asthma, atherosclerosis,Behcet's disease, bullous skin diseases, chronic obstructive pulmonarydisease (COPD), Crohn's disease, dermatitis, eczema, giant cellarteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatorybowel disease,), Kawasaki disease, lupus nephritis, multiple sclerosis,myocarditis, myositis, nephritis, organ transplant rejection,osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa,pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis,rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis systemiclupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis,type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, andWegener's granulomatosis.
 60. A method for treating a disease orcondition in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said disease or condition is selected from the group consistingof: diabetic nephropathy, hypertensive nephropathy, HIV-associatednephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focalsegmental glomerulosclerosis, membranous glomerulonephritis, minimalchange disease, polycystic kidney disease and tubular interstitialnephritis.
 61. A method for treating an acute kidney disease orcondition in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said acute kidney disease or condition is selected from thegroup consisting of: ischemia-reperfusion induced, cardiac and majorsurgery induced, percutaneous coronary intervention induced,radio-contrast agent induced, sepsis induced, pneumonia induced, anddrug toxicity induced.
 62. A method for treating an acquiredimmunodeficiency syndrome (AIDS) in a subject comprising administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof, to a subjectin need thereof.
 63. A method for treating a disease or condition in asubject comprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof, wherein saiddisease or condition is selected from the group consisting of: obesity,dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolicsyndrome, hepatic steatosis, type II diabetes, insulin resistance,diabetic retinopathy and diabetic neuropathy.
 64. A method ofcontraception in a male subject comprising administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof, to a malesubject in need thereof.